rs80357001
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_007294.4(BRCA1):c.692C>T(p.Thr231Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,612,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T231R) has been classified as Uncertain significance.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.692C>T | p.Thr231Met | missense_variant | 10/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.692C>T | p.Thr231Met | missense_variant | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000790 AC: 12AN: 151840Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000444 AC: 11AN: 247512Hom.: 0 AF XY: 0.0000521 AC XY: 7AN XY: 134326
GnomAD4 exome AF: 0.0000507 AC: 74AN: 1460648Hom.: 0 Cov.: 33 AF XY: 0.0000619 AC XY: 45AN XY: 726570
GnomAD4 genome AF: 0.0000790 AC: 12AN: 151840Hom.: 0 Cov.: 32 AF XY: 0.0000540 AC XY: 4AN XY: 74124
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 19, 2023 | 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) - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 14, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 09, 2022 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 12, 2023 | 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, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Likely benign, criteria provided, single submitter | curation | University of Washington Department of Laboratory Medicine, University of Washington | Mar 23, 2023 | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 22, 2017 | - - |
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Jun 20, 2002 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 29, 2017 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Nov 16, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 21, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at