Submissions for variant NM_007294.4(BRCA1):c.556T>G (p.Ser186Ala)

dbSNP: rs397509298

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000049055	SCV000077068	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 186 of the BRCA1 protein (p.Ser186Ala). This variant is present in population databases (rs397509298, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 12845657). ClinVar contains an entry for this variant (Variation ID: 55633). 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 expected to disrupt BRCA1 protein function. 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	RCV000579547	SCV000683335	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces serine with alanine at codon 186 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies reported to have examined this variant but the findings were inconclusive (PMID: 25823446, 30219179). This variant has been detected in at least four individuals affected with breast and/or ovarian cancer (PMID: 12845657, 30254663, 35409996; DOI: 10.1515/tjb-2019-0424) and in two individuals affected with colorectal cancer (PMID: 32658311). This variant has been identified in 1/250732 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.
Counsyl	RCV000662383	SCV000784785	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-12-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759562	SCV000888952	uncertain significance	not provided	2018-04-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000579547	SCV001186277	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-05	criteria provided, single submitter	clinical testing	The p.S186A variant (also known as c.556T>G), located in coding exon 7 of the BRCA1 gene, results from a T to G substitution at nucleotide position 556. The serine at codon 186 is replaced by alanine, an amino acid with similar properties. This alteration (designated as 675T>G) was detected in an individual who was diagnosed with breast cancer at 28 and whose father was diagnosed with leukemia at 63 (de Sanjosé S, et al. Int. J. Cancer 2003;106(4):588-93). In addition, this alteration was identified in a family who met a regional protocol for BRCA testing (Zuntini R et al. Front Genet, 2018 Sep;9:378). In another study, this alteration was seen in 0/732 breast cancer patients, 2/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). This amino acid position is highly 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.
GeneDx	RCV000759562	SCV002015521	uncertain significance	not provided	2021-11-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of BRCA1-related cancers (de Sanjose 2003, Zuntini 2018, Bahsi 2020); Published functional studies demonstrate reduced ubiquitine ligase activity (Starita 2015); Also known as 675T>G; This variant is associated with the following publications: (PMID: 12845657, 30254663, Bahsi2020[case report], 25823446)
MGZ Medical Genetics Center	RCV003607226	SCV004543882	likely benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR, PM2_SUP
Department of Medical and Surgical Sciences, University of Bologna	RCV000662383	SCV004228318	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-01	no assertion criteria provided	clinical testing	PM2(Supporting)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)