Submissions for variant NM_000059.4(BRCA2):c.9581C>A (p.Pro3194Gln)

gnomAD frequency: 0.00001  dbSNP: rs28897760

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045860	SCV000073873	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131306	SCV000186278	likely benign	Hereditary cancer-predisposing syndrome	2018-12-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
GeneDx	RCV001719713	SCV000210511	likely benign	not provided	2019-08-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22875147, 23704879, 18724707, 27223485, 21702907, 29116469, 27403073, 32854451)
Counsyl	RCV000031833	SCV000487802	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-11-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160173	SCV000600868	uncertain significance	not specified	2017-03-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131306	SCV000689208	likely benign	Hereditary cancer-predisposing syndrome	2017-06-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160173	SCV000917016	benign	not specified	2022-01-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9581C>A (p.Pro3194Gln) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251964 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9581C>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Palmero_2015, Brianese_2018). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.5266dupC, p.Gln1756Profs*74; BRCA2 c.3978_3979ins4, p.Ala1327fsX4) (BIC database and Brianese_2018), providing supporting evidence for a benign role. A recent case-control study showed that this variant is not associated with breast cancer (Dorling_2021). One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Tram_2013). Six other ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=4) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV003924879	SCV004746517	uncertain significance	BRCA2-related condition	2024-02-28	criteria provided, single submitter	clinical testing	The BRCA2 c.9581C>A variant is predicted to result in the amino acid substitution p.Pro3194Gln. This variant is predicted to abolish binding of the CDK2 kinase and creates a new binding site (Tram et al. 2013. PubMed ID: 23704879). This variant was also identified in individuals with a personal and family history of breast cancer and other hereditary cancer syndrome (Table S6, Hondow et al. 2011. PubMed ID: 21702907; Palmero et al. 2016. PubMed ID: 27223485). This variant is reported in 0.0028% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/38250/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Sharing Clinical Reports Project (SCRP)	RCV000031833	SCV000054441	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-02-08	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031833	SCV000147668	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing