Submissions for variant NM_007294.4(BRCA1):c.2312T>C (p.Leu771Ser)

gnomAD frequency: 0.00001  dbSNP: rs730881481

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159967	SCV000210126	uncertain significance	not provided	2020-09-22	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast or ovarian cancer as well as in a control population (Li 2013, Alvarez 2017, Momozawa 2018); Also known as 2431T>C; This variant is associated with the following publications: (PMID: 24321281, 30287823, 29088781, 30702160)
Ambry Genetics	RCV000163092	SCV000213597	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-08	criteria provided, single submitter	clinical testing	The p.L771S variant (also known as c.2312T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 2312. The leucine at codon 771 is replaced by serine, an amino acid with dissimilar properties. This alteration was identified in a cohort of Chilean breast cancer patients (Alvarez C et al. Oncotarget, 2017 Sep;8:74233-74243). This alteration was not observed with in 7,051 unselected female breast cancer patients or 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0001 in 12,490 male controls of Japanese ancestry. (Momozawa Y et al. Nat Commun, 2018 10;9:4083). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159967	SCV000296360	uncertain significance	not provided	2023-02-10	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251042 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 29088781 (2017)) and ovarian cancer (PMID: 24321281 (2013)). In addition, this variant has been reported in healthy control individuals (PMIDs: 30287823 (2018), 31214711 (2020), and 32980694 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000163092	SCV000683026	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-26	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with serine at codon 771 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 observed in an individual affected with ovarian cancer (PMID: 24321281) and a suspected hereditary breast and ovarian cancer family (PMID: 29088781). This variant also has been reported in breast, prostate and pancreatic cancer case-control studies in the Japanese population, in which this variant was detected in one unaffected individual in each study and absent in cancer cases (PMID: 30287823, 31214711, 32980694). This variant has been identified in 1/251042 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.
Invitae	RCV001061346	SCV001226084	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 771 of the BRCA1 protein (p.Leu771Ser). This variant is present in population databases (rs730881481, gnomAD 0.0009%). This missense change has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 24321281, 29088781, 30702160). ClinVar contains an entry for this variant (Variation ID: 182145). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000163092	SCV003847766	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479028	SCV004222750	uncertain significance	not specified	2023-11-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2312T>C (p.Leu771Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three 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 251042 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2312T>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g., Li_2013, Alvarez_2017). However the variant has also been reported in healthy controls (e.g., Momozawa_2018, Okawa_2023). These reports therefore 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 publications have been ascertained in the context of this evaluation (PMID: 29088781, 34981296, 24321281, 30287823, 36243179, 8723683). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Five submitters classified the variant as uncertain significance, and one submitter classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.