ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.692C>T (p.Thr231Met) (rs80357001)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000049098 SCV000077111 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-22 criteria provided, single submitter clinical testing
GeneDx RCV000586691 SCV000210082 uncertain significance not provided 2018-08-24 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.692C>T at the cDNA level, p.Thr231Met (T231M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). Using alternate nomenclature, this variant would be defined as BRCA1 811C>T. This variant has been observed in at least two individuals from high-risk breast and/or ovarian cancer families and was reported not to affect the expression level of full-length transcript, but was found to increase the level of a naturally occurring isoform in an RT-PCR based assay (van Harssel 2010, Brandao 2011). Additionally, Bouwman et al. (2013) concluded that BRCA1 Thr231Met is likely neutral based on an insensitivity to cisplatin and an ability to support cell growth similar to wild-type controls in a functional assay using BRCA1-deficient mouse embryonic stem cells. BRCA1 Thr231Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in a region known to interact with multiple proteins (Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Thr231Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000162837 SCV000213324 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-03 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 (van Harssel JJ et al. Fam. Cancer. 2010 Jun;9:193-201; Michils G et al. J. Mol. Diagn. 2012 Nov;14:623-30). This alteration has been reported with a carrier frequency of 0.00028 in 7051 unselected breast cancer patients and 0.00 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 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 2021-05-13 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). 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), 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. Three ClinVar submitters (evaluation after 2014) cite the variant as likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl RCV000112772 SCV000785508 uncertain significance Breast-ovarian cancer, familial 1 2017-08-29 criteria provided, single submitter clinical testing
Color Health, Inc 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 2020-08-12 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000586691 SCV001716314 uncertain significance not provided 2020-07-08 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112772 SCV000145665 uncertain significance Breast-ovarian cancer, familial 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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.