Submissions for variant NM_000059.4(BRCA2):c.3173A>G (p.Lys1058Arg)

gnomAD frequency: 0.00007  dbSNP: rs431825302

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724725	SCV000225162	uncertain significance	not provided	2015-04-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000724725	SCV000518279	likely benign	not provided	2020-08-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084692	SCV000549786	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000565270	SCV000661206	likely benign	Hereditary cancer-predisposing syndrome	2018-07-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000173966	SCV000694663	uncertain significance	not specified	2024-03-05	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3173A>G (p.Lys1058Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 246978 control chromosomes, predominantly at a frequency of 0.00021 within the Latino subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3173A>G has been reported in the literature in an individual affected with Breast Cancer (e.g., Diaz-Zabala_2018), however without strong evidence for causality (e.g., VUS classification by authors, lack of co-segregation and co-occurrence data). This report therefore does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 30400234). ClinVar contains an entry for this variant (Variation ID: 96786). Based on the evidence outlined above, including the lack of evidence in the literature supporting pathogenicity, the variant was classified as VUS-possibly benign.
Counsyl	RCV000082907	SCV000785778	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-11-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000565270	SCV000906058	likely benign	Hereditary cancer-predisposing syndrome	2018-10-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000724725	SCV001133743	uncertain significance	not provided	2023-01-03	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast or ovarian cancer (PMID: 29351780 (2018), 30400234 (2018)). The frequency of this variant in the general population, 0.00021 (7/33636 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000724725	SCV002048427	likely benign	not provided	2023-07-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000565270	SCV002533767	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-20	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000082907	SCV003843112	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2022-10-13	criteria provided, single submitter	clinical testing	The BRCA2 c.3173A>G (p.Lys1058Arg) missense change has a maximum subpopulation frequency of 0.021% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in at least one individual with breast cancer (PMID: 30400234). This variant is absent in the FLOSSIES database, which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000565270	SCV003851738	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Sharing Clinical Reports Project (SCRP)	RCV000082907	SCV000114981	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-03	no assertion criteria provided	clinical testing