Submissions for variant NM_007294.4(BRCA1):c.692C>T (p.Thr231Met)

gnomAD frequency: 0.00007  dbSNP: rs80357001

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000049098	SCV000077111	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000586691	SCV000210082	uncertain significance	not provided	2023-07-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: no effect on expression level of full-length transcript, but was found to increase the level of a naturally occurring isoform in an RT-PCR based assay, and demonstrated insensitivity to cisplatin and an ability to support cell growth similar to wild-type controls (Brandao et al., 2011; Bouwman et al., 2013); Observed in individuals with personal and/or family history of breast, ovarian, and other cancers (van Harssel et al., 2010; Brandao et al., 2011; Momozawa et al., 2018; Bakos et al., 2021; Delahunty et al., 2022); Also known as 811C>T; This variant is associated with the following publications: (PMID: 19949876, 29106415, 23867111, 16267036, 23034506, 21638052, 23893897, 25056543, 30287823, 31131967, 31853058, 35464868, 29360161, 33471991, 9582019, 9926942, 9788437, 20215511, 15385441, 32546644, 32467295, 32377563, 29884841, 34130653, 35263119, 34981296)
Ambry Genetics	RCV000162837	SCV000213324	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-12	criteria provided, single submitter	clinical testing	The p.T231M variant (also known as c.692C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 692. The threonine at codon 231 is replaced by methionine, an amino acid with similar properties. This variant has been reported in individuals undergoing breast cancer risk counseling and genetic testing and in an individual diagnosed with pancreatic cancer (van Harssel JJ et al. Fam. Cancer. 2010 Jun;9:193-201; Michils G et al. J. Mol. Diagn. 2012 Nov;14:623-30; Dudley B et al. Cancer, 2018 04;124:1691-1700). This alteration has been reported with a carrier frequency of 0.00028 in 7051 unselected breast cancer patients and was not identified in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083). In one study, RT-PCR analysis revealed partial exon 11 skipping, resulting in the production of full-length transcripts as well as increased expression of two isoforms that are also present in controls (Brandão RD et al. Breast Cancer Res. Treat. 2011 Oct;129:971-82; Ambry internal data). In one cDNA-based functional assay, this alteration was predicted to be neutral (Bouwman P et al. Cancer Discov. 2013 Oct;3:1142-55). In addition, this alteration was classified as uncertain significance based on a multifactorial analysis model of variant classification (Parsons MT et al. Hum. Mutat. 2019 09;40:1557-1578). Of note, this alteration is also designated as 811C>T in some published literature. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175367	SCV000699293	uncertain significance	not specified	2023-09-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.692C>T (p.Thr231Met) 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 4.4e-05 in 247512 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (4.4e-05 vs 0.001), allowing no conclusion about variant significance. c.692C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and pancreatic cancer (e.g. Judkins_2005, van Harssel_2010, Brandao_2011, Dudley_2018, Momozawa_2018, Dorling_2021, Delahunty_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with pathogenic variants have been reported (BRCA2 c.8364G>A, p.Trp2788*; CHEK2 c.1100delC, p.Thr367Metfs*15; LOVD and BRCA2 c.8755-1G>A, Bakos_2021), providing supporting evidence for a benign role. Two independent studies have shown that this variant does not affect the expression level of the full length transcript but gives rise to increased expression of a naturally occurring isoform lacking exon 11, the consequence of which is unknown (Brandao_2011, Tammaro_2014). Using different assays to assess the ability of variants to complement Brca1-deficient mouse embryonic stem cells in homologous recombination DNA repair (HRR), Bouwman et al (2013 and 2020) determined c.692C>T to be neutral. A recent publication involving the ENIGMA network of collaborators (Parsons_2019) assigned a classification of uncertain significance based on likelihood ratios (LRs) for pathogenicity estimated from clinical data of co-occurrence, family history and bioinformatic predictions. However, Bouwman et al (2020) using multifactorial likelihood analysis from their study combined with Parsons_2019 study determined the variant of interest to have very low posterior probability of being pathogenic. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as VUS (n=5) and Likely Benign (n=4). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Counsyl	RCV000112772	SCV000785508	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-08-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162837	SCV000910852	likely benign	Hereditary cancer-predisposing syndrome	2017-01-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586691	SCV001133643	likely benign	not provided	2023-08-14	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000586691	SCV001716314	uncertain significance	not provided	2022-12-09	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000049098	SCV002026011	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000162837	SCV003848011	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).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112772	SCV000145665	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-06-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000586691	SCV001552645	uncertain significance	not provided		no assertion criteria provided	clinical testing