Submissions for variant NM_007294.4(BRCA1):c.508C>T (p.Arg170Trp)

gnomAD frequency: 0.00001  dbSNP: rs80357325

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112723	SCV001161597	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000759
Invitae	RCV000048786	SCV000076799	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000132127	SCV000187195	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-01	criteria provided, single submitter	clinical testing	The p.R170W variant (also known as c.508C>T), located in coding exon 6 of the BRCA1 gene, results from a C to T substitution at nucleotide position 508. The arginine at codon 170 is replaced by tryptophan, an amino acid with dissimilar properties. Functional analysis of this alteration using cDNA-based functional complementation assays in mouse embryonic stem cells demonstrated that this alteration resulted in similar proliferation rates as wildtype, and was not deleterious based on cisplatin sensitivity assays (Bouwman P et al. Cancer Discov 2013 Oct; 3(10):1142-55). This alteration was not observed in unselected male breast cancer patients but was observed with an allele frequency of 0.0001 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This variant was also reported in 2/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
GeneDx	RCV000483759	SCV000566762	uncertain significance	not provided	2021-08-10	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 has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history including breast and ovarian cancers (Tung 2015); Published functional studies demonstrate no damaging effect to cell growth, ubiquitination, or sensitivity to cisplatin (Bouwman 2013, Starita 2015); This variant is associated with the following publications: (PMID: 23867111, 25823446, 25186627, 30287823, 33087888, 23983145, 10923033, Rodriguez2013[CaseReport], 31131967)
Counsyl	RCV000112723	SCV000784865	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-01-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132127	SCV000911724	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 170 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).Functional studies have reported that this variant does not impact BRCA1 in on growth and homology-directed DNA repair assays in mouse Brca1-null embryonic stem cells (PMID: 23867111, 32546644). This variant has been reported in an individual affected with breast cancer (PMID: 25186627) and in a breast cancer case-control meta-analysis in 2/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001411). This variant also has been reported in a breast cancer case-control study and a pancreatic cancer case-control study in which this variant is absent in cases and found only in one unaffected individual in the control cohort (PMID: 30287823, 32980694). A multifactorial analysis has reported likelihood ratios for pathogenicity based on tumor pathology, co-occurrence with a pathogenic variant and family history of 0.544, 1.0673, 0.0641, respectively (PMID: 31131967). This variant has been identified in 3/251458 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483759	SCV001133607	uncertain significance	not provided	2019-05-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255589	SCV001432091	uncertain significance	not specified	2020-08-10	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.508C>T (p.Arg170Trp) 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 1.2e-05 in 251458 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.508C>T has been reported in the literature in individuals affected with Breast Cancer (example, Tung_2014) as well as an unaffected Japanese male control (Momozawa_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Bouwman_2013). These results showed no damaging effect of this variant based on cisplatin response. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). Six clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All clinical diagnostic laboratories classify the variant as VUS while the expert panel has settled upon a definitive classification as Benign based on posterior probability from multifactorial likelihood analysis (Plon_2008). Based on the evidence outlined above, until the consensus interpretation converges to a neutral/benign outcome, the variant was classified as uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001255589	SCV004242850	benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112723	SCV000145603	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000483759	SCV001549629	uncertain significance	not provided		no assertion criteria provided	clinical testing