Submissions for variant NM_007294.4(BRCA1):c.693G>A (p.Thr231=)

gnomAD frequency: 0.00011  dbSNP: rs62625298

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000144222	SCV000578247	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Invitae	RCV001080079	SCV000077112	benign	Hereditary breast ovarian cancer syndrome	2024-01-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131383	SCV000186359	likely benign	Hereditary cancer-predisposing syndrome	2022-03-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000588682	SCV000210083	uncertain significance	not provided	2023-05-11	criteria provided, single submitter	clinical testing	Also known as 812G>A; This variant is associated with the following publications: (PMID: 24569164, 19370767, 26913838, 30287823, 25056543, 20104584, 21638052, 12890739, 16835750, 21702907, 28726806, 22615956, 31422574, 34597585, 32467295, 35402282, 35477782, 22817731, 29884841)
Michigan Medical Genetics Laboratories, University of Michigan	RCV000144222	SCV000267686	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-21	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000159943	SCV000538446	uncertain significance	not specified	2016-03-29	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Silent, not in splice site. ExAC: 1/5842 Finnish chromosomes; ClinVar: 2 labs B/LB, 2 labs VUS; 1 paper investigating constraint against synonymous substitutions in BRCA exon 11
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588682	SCV000600433	likely benign	not provided	2023-05-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000159943	SCV000699294	likely benign	not specified	2020-01-31	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.693G>A results in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, multiple publications reports experimental evidence that this variant affects mRNA splicing, with the variant determining exon 11 skipping and a marked increase in amounts of the D(11) isoform (Brandao_2011, Raponi_2012, Tammaro_2014). The physiological consequences of this alteration are unknown since exon 11 skipping also occurs in normal breast tissue. The variant allele was found at a frequency of 6.9e-05 in 247680 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (6.9e-05 vs 0.001), allowing no conclusion about variant significance. c.693G>A has been reported in the literature in sequencing studies of individuals affected with Hereditary Breast and Ovarian Cancer (example, Borg_2010, Brandao_2011, Song_2006, Momozawa_2018, Kraemer_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. One recently published case control association study of Japanese individuals showed no association of this variant with breast cancer in males and females (Momozawa_2019). At-least one co-occurrence with another pathogenic variant has been reported in the UMD database (BRCA2 c.6082_6086delGAAGA, p.Glu2028LysfsX19), providing supporting evidence for a benign role. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign, n=2; likely benign, n=2; VUS, n=4). Some of these submitters provide overlapping evidences utilized in the context of this evaluation. We have observed this variant at a frequency of 0.01% in our tested cohort and previously classified the variant as a VUS weighting the reported splicing evidence in our evaluation. However, in over two years since its initial evaluation, we have not observed any additional evidence supporting a pathogenic outcome and at-least one additional report supporting no association with breast cancer has been ascertained (Momozawa_2018). Based on the evidence outlined above, the variant was re-classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000131383	SCV000902683	likely benign	Hereditary cancer-predisposing syndrome	2014-12-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588682	SCV001501184	likely benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	BRCA1: BP4, BP7
Sema4, Sema4	RCV000131383	SCV002537891	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-23	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000159943	SCV002551043	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001080079	SCV004014982	likely benign	Hereditary breast ovarian cancer syndrome	2023-05-16	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000144222	SCV004016747	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554691	SCV004752831	likely benign	BRCA1-related disorder	2019-09-26	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Sharing Clinical Reports Project (SCRP)	RCV000144222	SCV000189350	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2011-03-02	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353729	SCV000591297	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Thr231= variant was identified in 5 of 20638 proband chromosomes (frequency: 0.0002) from individuals or families with breast and ovarian cancer and was present in 5 of 47462 control chromosomes (frequency: 0.0001) from healthy individuals (Momozawa 2018, Borg 2010, Brandao 2011, Song 2006). The variant was also identified in dbSNP (ID: rs62625298) as "With Likely benign, Uncertain significance allele", ClinVar (classified as uncertain significance by GeneDx and 5 other submitters; as likely benign by ENIGMA expert panel in 2017 and Ambry Genetics; and as benign by Invitae and 2 other submitters), LOVD 3.0 and in UMD-LSDB (15 records, neutral classification). In UMD, the variant was reported as co-occurring with a pathogenic BRCA2 variant (c.6082_6086del, p.Glu2028Lysfs*19), increasing the likelihood that the p.Thr231= variant does not have clinical significance. It was identified in control databases in 22 of 274654 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 23876 chromosomes (freq: 0.00004), Other in 1 of 6404 chromosomes (freq: 0.0002), Latino in 2 of 34158 chromosomes (freq: 0.00006), European in 14 of 125226 chromosomes (freq: 0.0001), and Finnish in 4 of 25642 chromosomes (freq: 0.0002), while it was not observed in the Ashkenazi Jewish, East Asian or South Asian populations. This variant was demonstrated to result in partial exon 11 skipping by RT-PCR and mini-gene assays, although the biological significance of the change in the ratio of splicing isoforms is unclear (Brandao 2011, Raponi 2012, Tammaro 2015). The p.Thr231= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. However, 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
True Health Diagnostics	RCV000131383	SCV000805236	uncertain significance	Hereditary cancer-predisposing syndrome	2018-04-06	no assertion criteria provided	clinical testing