Submissions for variant NM_007294.4(BRCA1):c.2518A>G (p.Ser840Gly)

gnomAD frequency: 0.00004  dbSNP: rs377475866

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167194	SCV000218031	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-10	criteria provided, single submitter	clinical testing	The p.S840G variant (also known as c.2518A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 2518. The serine at codon 840 is replaced by glycine, an amino acid with similar properties. In one study, this alteration was detected in 1/1398 patients with unilateral breast cancer and in none of the 705 patients tested with contralateral breast cancer (Borg, A et al. Hum Mutat. 2010 Mar;31(3):E1200-40). This amino acid position is poorly 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.
Invitae	RCV000232315	SCV000289761	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 840 of the BRCA1 protein (p.Ser840Gly). This variant is present in population databases (rs377475866, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 187463). 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 BRCA1 protein function with a negative predictive value of 95%. 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.
GeneDx	RCV000759508	SCV000321420	uncertain significance	not provided	2023-11-10	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer (PMID: 20104584); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 2637A>G; This variant is associated with the following publications: (PMID: 21520273, 20104584, 15343273)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759508	SCV000888869	uncertain significance	not provided	2019-01-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000167194	SCV000909341	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-18	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 840 of the BRCA1 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: 20104584) and also in an individual with a pathogenic BRCA1 co-variant but the individual's cancer health history was not provided (ClinVar: SCV001361737.1). This variant has been identified in 1/251094 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	RCV001193116	SCV001361737	uncertain significance	not specified	2019-12-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2518A>G (p.Ser840Gly) 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 4e-06 in 251094 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2518A>G has been reported in the literature in an individual affected with unilateral breast cancer (Borg 2010, Capanu 2011). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with anoother pathogenic variant has been observed at our laboratory ( BRCA1 c.3756_3759delGTCT , p.Ser1253fsX10), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000167194	SCV003847611	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).