Submissions for variant NM_000059.4(BRCA2):c.5893C>T (p.Leu1965Phe)

gnomAD frequency: 0.00002  dbSNP: rs398122542

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215394	SCV000274563	likely benign	Hereditary cancer-predisposing syndrome	2019-02-04	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657041	SCV000296533	uncertain significance	not provided	2023-03-09	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00014 (5/34586 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with breast cancer (PMID: 18284688 (2008)). 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.
GeneDx	RCV000657041	SCV000567176	uncertain significance	not provided	2022-12-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 6121C>T; This variant is associated with the following publications: (PMID: 18284688)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637433	SCV000758892	likely benign	Hereditary breast ovarian cancer syndrome	2024-12-19	criteria provided, single submitter	clinical testing
Counsyl	RCV000076944	SCV000784947	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-02-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000215394	SCV001352020	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 1965 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 18284688). This variant has been identified in 5/250956 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155065	SCV003844243	uncertain significance	not specified	2024-03-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5893C>T (p.Leu1965Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250956 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5893C>T has been reported in the literature in individuals affected with Breast Cancer without evidence of cosegregation (Lee_2008, Zayas-Villanueva_2019). These report(s) do 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 publications have been ascertained in the context of this evaluation (PMID: 18284688, 31331294). ClinVar contains an entry for this variant (Variation ID: 91427). Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000215394	SCV003850759	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).
All of Us Research Program, National Institutes of Health	RCV004804047	SCV004846663	uncertain significance	BRCA2-related cancer predisposition	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 1965 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 18284688). This variant has been identified in 5/250956 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000657041	SCV005876692	likely benign	not provided	2024-03-11	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000076944	SCV000108741	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-04-18	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732648	SCV005359528	uncertain significance	BRCA2-related disorder	2024-07-17	no assertion criteria provided	clinical testing	The BRCA2 c.5893C>T variant is predicted to result in the amino acid substitution p.Leu1965Phe. This variant has been reported in individual(s) with breast cancer (see for example, Suppl Table 2. Lee et al 2008. PubMed ID: 18284688). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as a variant of uncertain significance or likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/91427/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.