17-43124044-A-G
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong
The NM_007294.4(BRCA1):c.53T>C(p.Met18Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461388Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4AN XY: 727020
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5Uncertain:1Other:1
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IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.99829 -
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not provided Pathogenic:6
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This variant is denoted BRCA1 c.53T>C at the cDNA level, p.Met18Thr (M18T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). Using alternate nomenclature, this variant would be defined as BRCA1 172T>C. BRCA1 Met18Thr has been observed in multiple individuals with breast or ovarian cancer, including male breast cancer (Langston 1996, Greenman1998, Malone 1998, van Orsouw 1999), and was reported to segregate with disease in two kindreds (Mohammadi 2009). This variant was predicted by Lindor et al. (2012) to likely be pathogenic based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious variants. Functional studies have found discordant results with respect to ubiquitin ligase activity and BARD1 binding, but have revealed impaired homology-directed repair activity, increased centrosome amplification, and loss of ability to rescue cell growth (Ruffner 2001, Morris 2004, Morris 2006, Sarkar 2008, Ransburgh 2010, Parvin 2011, Kais 2012, Bouwman 2013, Towler 2013, Starita 2015). BRCA1 Met18Thr was not observed in large population cohorts (Lek 2016). This variant is located in the RING domain and a region that binds BRD7 and BARD1 (Narod 2004, Borg 2010, Harte 2010, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available information, we consider BRCA1 Met18Thr to be a likely pathogenic variant. -
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It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 8531967 (1996), 9544766 (1998), 9523200 (1998), 19563646 (2009), 25893891 (2015), 33471991 (2021)) and ovarian cancer (PMID: 10528853 (1999), 30078507 (2018)). Published functional studies have shown that this variant results in a deleterious effect on BRCA1 protein function (PMID: 11320250 (2001), 23161852 (2013), 23867111 (2013), 25823446 (2015), 30209399 (2018)). Based on the available information, this variant is classified as pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:4
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 18 of the BRCA1 protein (p.Met18Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 8531967, 9523200, 9544766, 10528853, 16683254, 28888541, 31907386). This variant is also known as c.172T>C. ClinVar contains an entry for this variant (Variation ID: 37664). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20103620, 21725363, 23161852, 23867111, 25823446, 27272900). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Data included in classification: The variant was observed in 7 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing was 25,773. Case control comparison against ethnically matched population data (7/25,773 in familial cases against 0/56,696 GNOMAD NFE controls pexact= 0.00029 (PS4_VS). The variant is absent in the remainder of the GNOMAD populations (68,846 individuals) (PM2_mod). Non-functional in SGE haploid BRCA1-assay (Findlay et al. 2018) (PS3_strong). Classified as Likely Pathogenic by Ambry 2018, Gene Dx 2014, Counsyl 2018 Color LP 2018 (PP5_sup). Data not included in classification: Predicted deleterious on SIFT and Align GVGD. Predicted benign on Polyphen HumVar. There are additional reports of this variant in ClinVar (5), BIC (3) and BRCA1 LOVD (11), UMD(7), DMuDB(7). -
Variant summary: BRCA1 c.53T>C (p.Met18Thr) results in a non-conservative amino acid change located in the Zinc finger, RING-type domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 254472 control chromosomes (ACMG, PM2). c.53T>C has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (ACMG, PS4). These data indicate that the variant is very likely to be associated with disease. In functional analyses, multiple studies have reported deleterious effects of the variant, including centrosome amplification, defective BRCA1-mediated homologous repair, defective double-strand break repair, and defective homology-directed recombination (HDR) (Kais_2013, Parvin_2011, Ransburgh_2010, Towler_2013) (ACMG, PS3). In addition, multifactorial probability models have predicted the variant to be likely pathogenic or pathogenic (Lindor_2012, Easton_2007, Parsons_2019). Six submitters including an expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
The p.Met18Thr variant in BRCA1 has been reported at least 6 individuals with BRCA1-related cancers and segregated with disease in at least 2 affected relatives from 2 families (Malone 1998, Van Orsouew 1999, Mohammadi 2009). It was absent from large population studies, but has been reported in ClinVar (Variation ID: 37664). Computational prediction tools and conservation analyses are consistent with pathogenicity. In vitro functional studies are conflicting as to the effect of this variant on protein function (Ruffner 2001, Easteron 2007, Sarkar 2008, Millot 2011, Ransburgh 2010, Parvin 2011, Kais 2012, Lindor 2012, Bouwman 2013, Towler 2013, Whiley 2014, Starita 2016, Thouvenot 2016, Findlay 2018); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and ovarian cancer. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP3, PS3_Supporting. -
Hereditary cancer-predisposing syndrome Pathogenic:2
The p.M18T variant (also known as c.53T>C), located in coding exon 1 of the BRCA1 gene, results from a T to C substitution at nucleotide position 53. The methionine at codon 18 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in numerous early-onset breast and/or ovarian cancer patients and has been associated with a significant reduction in homologous-directed recombination activity compared with wild type BRCA1 (p<0.001) (Langston AA et al. N. Engl. J. Med. 1996; 334:137-42, Greenman J et al. Genes Chromosomes Cancer 1998; 21:244-9, Malone KE et al. JAMA 1998; 279:922-9, Ransburgh DJ et al. Cancer Res., 2010 Feb;70:988-95; Towler WI et al. Hum. Mutat. 2013; 34:439-45). This alteration also demonstrated reduced ubiquitin ligase activity and BARD1 binding activity as compared to wild type (Whiley PJ et al. PLoS ONE, 2014 Jan;9:e86836; Starita LM et al. Genetics. 2015 Jun;200(2):413-22). An additional functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
This missense variant replaces methionine with threonine at codon 18 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Multiple functional studies have reported that this variant impacted BRCA1 function in homology-directed repair and cell proliferation assays (PMID: 21372787, 23867111, 24489791, 30219179, 30209399). This variant has been detected in at least seven individuals affected with breast and ovarian cancer (PMID: 8531967, 9523200, 10528853, 20103620, 25893891, 30078507; BIC accession number 3074), and it has also been reported to segregate with disease in carrier families (PMID: 19563646, 31131967) and has a family history likelihood ratio for pathogenicity of 25.4786 (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -
Inherited ovarian cancer (without breast cancer) Pathogenic:1
PS3,PS4_Very Strong,PM2,PP3,PP4_Strong -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at