Submissions for variant NM_000059.4(BRCA2):c.6554C>T (p.Ala2185Val)

dbSNP: rs980859921

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000574498	SCV000668841	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-25	criteria provided, single submitter	clinical testing	The p.A2185V variant (also known as c.6554C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 6554. The alanine at codon 2185 is replaced by valine, an amino acid with similar properties. This alteration has been reported in 1/349 Brazilian high-risk breast/ovarian cancer families, and the proband carrying this variant was diagnosed with breast cancer at age 31 and had two close relatives with breast cancer (Fernandes GC et al. Oncotarget, 2016 Dec;7:80465-80481). In addition, this alteration was detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000574498	SCV000688986	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 2185 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 individuals affected with breast cancer (PMID: 27741520, 32986223). This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000709328	SCV000952384	likely benign	Hereditary breast ovarian cancer syndrome	2023-10-14	criteria provided, single submitter	clinical testing
Mendelics	RCV004701665	SCV001139153	likely benign	Hereditary cancer	2024-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000989053	SCV003807777	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-01-20	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderated
University of Washington Department of Laboratory Medicine, University of Washington	RCV000574498	SCV003847267	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).
PreventionGenetics, part of Exact Sciences	RCV004527661	SCV004107173	uncertain significance	BRCA2-related disorder	2023-06-01	criteria provided, single submitter	clinical testing	The BRCA2 c.6554C>T variant is predicted to result in the amino acid substitution p.Ala2185Val. This variant has been reported and classified as a variant of uncertain significance in patients with breast cancer (Fernandes et al. 2016. PubMed ID: 27741520; Bandeira et al. 2020. PubMed ID: 32986223). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV000989053	SCV004844280	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 2185 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 individuals affected with breast cancer (PMID: 27741520, 32986223). This variant has not been identified 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.