Submissions for variant NM_000059.4(BRCA2):c.10045A>G (p.Thr3349Ala)

gnomAD frequency: 0.00010  dbSNP: rs80358387

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031300	SCV000244416	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000000919
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086443	SCV000071718	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000759571	SCV000210695	benign	not provided	2019-10-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25637381, 21120943, 26420498, 10755399, 18403564, 22505045, 24323938, 21520273, 20104584, 12955716, 11979449, 25682074, 25348012, 17924331, 21990134, 29988080, 32123317)
Ambry Genetics	RCV000163020	SCV000213508	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Vantari Genetics	RCV000163020	SCV000267028	likely benign	Hereditary cancer-predisposing syndrome	2016-02-04	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000043705	SCV000538477	likely benign	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 5/11516 Latino; ClinVar: 4 B/LB, 1 VUS
Color Diagnostics, LLC DBA Color Health	RCV000163020	SCV000683390	likely benign	Hereditary cancer-predisposing syndrome	2015-06-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000043705	SCV000694490	benign	not specified	2020-09-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.10045A>G (p.Thr3349Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251290 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00012 vs 0.00075), allowing no conclusion about variant significance. c.10045A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence of causality. One patient with the variant showed retention of the wild-type allele and loss of the allele harbouring the variant, suggesting the variant is not deleterious (Osorio_2002). Multifactorial models that incorporate family history, co-segregation, co-occurrence, and tumor pathology has predicted the variant to be likely neutral (Easton_2007, Lindor_2012). Multiple publications report experimental evidence evaluating an impact on protein function: splicing is not affected (Houdayer_2012) and HDR and cell survival assays show no difference from WT controls (Mesman_2018), altogether suggesting the variant has no effect on protein function. Seven clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as benign (n=3)/likely benign (n=5). Several submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759571	SCV000888967	benign	not provided	2023-05-05	criteria provided, single submitter	clinical testing
Mendelics	RCV000031300	SCV001139283	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163020	SCV002533184	likely benign	Hereditary cancer-predisposing syndrome	2021-02-03	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000031300	SCV004846256	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-01	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000043705	SCV005090080	benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031300	SCV000053905	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2008-01-08	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031300	SCV000145744	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148421	SCV000190120	likely benign	Breast neoplasm	2014-06-01	no assertion criteria provided	research
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000043705	SCV001905898	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000043705	SCV001958277	benign	not specified		no assertion criteria provided	clinical testing