Palb2 Ashley with POG vs Czech/Slovak Study
Ashley’s PALB2 from POG at BC Cancer Agency - Vancouver, BC
https://open.library.ubc.ca/media/download/pdf/24/1.0394119/4
https://www.nature.com/articles/s41436-020-0880-8.pdf
Ashley is Case 13 in links above. Top PDF doc pages 96, 103, 200
NM_024675.3(PALB2):c.2835- 282_3113+1377del
PALB2 exons 9-10 pathogenic deletion (PVS1, PM2)
moderate-penetrance breast cancer susceptibility
deletion of 3423 bp
16p12: 23,631,306 - 23,634,733 (DELLY)
16p12: 23,631,313 - 23,634,736 (Manta)
Potential: 16: 23621352-23623140 (GRCh38) GRCh38 UCSC
16: 23632673-23634461 (GRCh37) GRCh37 UCSC
Mentioned from Invitae:
https://www.ncbi.nlm.nih.gov/clinvar/variation/417514/?new_evidence=false#id_first
https://www.ncbi.nlm.nih.gov/clinvar/variation/652951/?new_evidence=false#id_first
December 8, 2021
Dear Brian Shirts,
Further to the email I just sent that is below…
This is what Color sent me when I asked in 2020 for ClinVar info… documented in 2016 submitted by Invitae:
https://www.ncbi.nlm.nih.gov/clinvar/variation/417514/?new_evidence=false#id_first
And then the one you shared on my Connect my Variant page which was input onto ClinVar in Feb 2020 as a case through Invitae:
https://www.ncbi.nlm.nih.gov/clinvar/variation/652951/?new_evidence=false#id_first
I find it interesting that the base points affected are so much smaller when mine and the Prague journal documents it so much larger at 3423 and 3424bp.
So why the heck would Invitae document this but not Color? It drives me nuts that my variant is not on there.
Ash
(Note: Ashley matched the Slovak but the ones listed below could be variants of this original mutation to others from what is listed above. Brian regards below and confirms the Prage/Czech version matches with Ashley/me)
Hi Ashley,
Thanks for sending this. I will update the ConnectMyVariant page with the breakpoints.It took me a little digging, but as far as I can tell these are the same thing. It looks to me like the reason the breakpoints are listed different is that the Czech/Slovak paper lists a C>G change 2 bp after the deletion. I bet that the people working on your deletion included that base pair in the deletion. Usually one assumes that two changes so close together are part of the same large deletion and lists it as one event. There are alternative ways to list this, such as an indel with 3428 bp deleted and one or two inserted. Sometimes the sequence is not entirely clear due to read mapping issues, so researchers do the best that they can. So, I can’t with absolute certainty that these are the same thing without seeing the sequences from both papers, but all things considered it really looks like the same deletion with different people annotating it differently.The interview went well. I will let you know when they tell me it is coming out. Thanks for the permission to tell your story. I think that it is a compelling story. Hopefully it will help us find your relatives and motivate others to follow your example in advocating for cancer prevention. I’ll continue to share your story in hopes that someone with your variant will come out of the woodwork.Best regards,Brian
VS
Czech/Slovak Study:
https://databases.lovd.nl/shared/variants/0000080196#00015623
c.2835-281_3113+1374del
With help from Marc Tischkowitz
Listed by three family in total. This is one.
https://cebp.aacrjournals.org/content/22/12/2323
p.A946_W1038del
A deletion comprising exons 9–10 (Fig. 2B) was identified in an HBC family (#1507) with three cases of breast cancer. With PCR primers located in introns 7 and 11 (Supplementary Table S1), an extra fragment of 6779 bp was amplified from the patient’s DNA but not from control DNA. The sequencing of this PCR product dem- onstrated a deletion of 3424 bp and a substitution of C to G at position the g.26372 of intron 10 (g.22947_26370del3424, 26372C>G). Breakpoints were located in a sequence containing 16 identical nucleotides within AluSx3 and AluSz6 repeats in intron 8 and 10, respectively. Although the deletion of exons 9–10 maintains the PALB2 reading frame, an elimination of the gene region coding for 93 amino acids (p.A946_W1038del) that interfere with WD- 40 domains essential for BRCA2 binding (residues 850– 1186; ref. 49) may be considered pathogenic.
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CLICK Images for screenshots from Czech as well as POG/UBC of Ashley’s mutation from links listed above:
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