Submissions for variant NM_000059.4(BRCA2):c.8993C>T (p.Ser2998Phe)

dbSNP: rs587780664

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122937	SCV000166195	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 2998 of the BRCA2 protein (p.Ser2998Phe). This variant is present in population databases (rs587780664, gnomAD 0.006%). This missense change has been observed in individual(s) with a personal or family history of cancer (PMID: 26207792). ClinVar contains an entry for this variant (Variation ID: 135819). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Ambry Genetics	RCV000570751	SCV000668766	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-15	criteria provided, single submitter	clinical testing	The p.S2998F variant (also known as c.8993C>T), located in coding exon 22 of the BRCA2 gene, results from a C to T substitution at nucleotide position 8993. The serine at codon 2998 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been reported in a cohort of 1105 individuals tested using a 29-gene next-generation sequencing panel (Lincoln SE et al. J Mol Diagn, 2015 Sep;17:533-44). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000570751	SCV000684013	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 2998 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 with a personal or family history of cancer (PMID: 26207792). This variant has been identified in 1/250772 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.
GeneDx	RCV003313039	SCV004012544	uncertain significance	not provided	2023-01-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 9221C>T; Observed in an individual referred for multi-gene panel testing for a personal and/or family history suggestive of hereditary breast and ovarian cancer (Lincoln et al., 2015); This variant is associated with the following publications: (PMID: 29884841, 32377563, 12228710, 26207792)
All of Us Research Program, National Institutes of Health	RCV003997395	SCV004846103	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 2998 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 with a personal or family history of cancer (PMID: 26207792). This variant has been identified in 1/250772 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	RCV004525875	SCV005040042	uncertain significance	not specified	2024-03-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8993C>T (p.Ser2998Phe) results in a non-conservative amino acid change located in the BRCA2, OB2 domain (IPR048262) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250772 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8993C>T has been reported in the literature as a VUS in settings of multigene panel testing among individuals affected with breast and/or ovarian cancer (example, Tung_2015). 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 publication have been ascertained in the context of this evaluation (PMID: 26207792). ClinVar contains an entry for this variant (Variation ID: 135819). Based on the evidence outlined above, the variant was classified as uncertain significance.