Submissions for variant NM_000059.4(BRCA2):c.7618C>A (p.Leu2540Met)

gnomAD frequency: 0.00002  dbSNP: rs397507390

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166080	SCV000216843	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-06	criteria provided, single submitter	clinical testing	The p.L2540M variant (also known as c.7618C>A) is located in coding exon 15 of the BRCA2 gene. The leucine at codon 2540 is replaced by methionine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 15. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000545892	SCV000635595	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2540 of the BRCA2 protein (p.Leu2540Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 38111). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000166080	SCV001344656	uncertain significance	Hereditary cancer-predisposing syndrome	2019-08-01	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with methionine at codon 2540 of the BRCA2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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	RCV002265573	SCV002547597	uncertain significance	not specified	2022-05-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473211	SCV004211920	uncertain significance	Familial cancer of breast	2024-03-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031693	SCV004844441	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with methionine at codon 2540 of the BRCA2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998122	SCV005625292	uncertain significance	not provided	2023-10-10	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031693	SCV000054300	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-01-30	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532457	SCV004712827	uncertain significance	BRCA2-related disorder	2023-11-30	no assertion criteria provided	clinical testing	The BRCA2 c.7618C>A variant is predicted to result in the amino acid substitution p.Leu2540Met. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38111/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.