rs80357276
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3PP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.122A>T variant in BRCA1 is a missense variant predicted to cause substitution of histidine by leucine at amino acid 41 (p.(His41Leu)). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.56, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.00 predicts no impact on splicing (score threshold ≤0.1). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMID:30209399, 35659930). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.78 (based on family history), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID:31853058). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PP3, PS3, PM2_Supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10580711/MONDO:0700268/092
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
Publications
- breast-ovarian cancer, familial, susceptibility to, 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- Fanconi anemia, complementation group SInheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
- pancreatic cancer, susceptibility to, 4Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.122A>T | p.His41Leu | missense_variant | Exon 3 of 23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.122A>T | p.His41Leu | missense_variant | Exon 3 of 23 | 1 | NM_007294.4 | ENSP00000350283.3 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 30
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:2
This variant is denoted BRCA1 c.122A>T at the cDNA level, p.His41Leu (H41L) at the protein level, and results in the change of a Histidine to a Leucine (CAC>CTC). Using alternate nomenclature, this variant would be defined as BRCA1 241A>T. Functional interrogation of BRCA1 His41Leu by yeast-hybrid assay demonstrates impaired interaction between the variant and E2 (UbcH5a) in comparison to wild type (Morris 2006). In addition, a less severe, conservative amino acid change BRCA1 His41Arg (H41R) was predicted to be pathogenic by a multifactorial model based on pathology, species conservation and familial co-segregation, was deficient in a single strand annealing assay, has been associated with centrosome amplification, was non-functional in a homology-directed recombination (HDR) assay and exhibited decreased BARD1 binding and ubiquitin ligase activity (Whiley 2014, Towler 2013, Kais 2012, Ransburgh 2010, Morris 2006). BRCA1 His41Leu was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Histidine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 His41Leu occurs at a position that is conserved in mammals and is located in the RING-finger domain and Ub site, as well as a region known to interact with multiple other proteins (Wu 1996, Narod 2004, Borg 2010, Harte 2010, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider BRCA1 His41Leu to be a likely pathogenic variant. -
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in a woman affected with breast cancer (PMID: 25186627 (2015)). Functional studies have shown that this variant causes loss of DNA repair activity and reduced cellular survival (PMID: 30209399 (2018), 30219179 (2018)), as well as reduced E3 ligase activity (PMID: 25823446 (2015)). Based on the available information, this variant is classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
The p.H41L pathogenic mutation (also known as c.122A>T), located in coding exon 2 of the BRCA1 gene, results from an A to T substitution at nucleotide position 122. The histidine at codon 41 is replaced by leucine, an amino acid with similar properties. One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay. (Findlay GM et al. Nature. 2018 10;562:217-222). Substitutions at this amino acid residue severely impact E3 ubiquitin ligase activity, however, they have minimal impact on BARD1 binding (Morris JR et al. Hum Mol Genet. 2006 Feb;15(4):599-606; Starita LM et al. Genetics. 2015 Jun;200:413-22). Several other substitutions at this amino acid position are pathogenic, including arginine and tyrosine (Ambry internal data; Morris JR et al. Hum. Mol. Genet. 2006 Feb; 15(4):599-606; Ransburgh DJ et al. Cancer Res. 2010 Feb; 70(3):988-95; Towler WI et al. Hum. Mutat. 2013 Mar; 34(3):439-45). This variant affects a known zinc binding motif which is predicted to disrupt protein folding (Ambry internal data; Brzovic PS et al. Nat. Struct. Biol. 2001 Oct;8:833-7; Brzovic PS et al. Proc. Natl. Acad. Sci. U.S.A., 2003 May;100:5646-51). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
This missense variant replaces histidine with leucine at codon 41 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant is non-functional in a homology-direct repair assay (PMID: 30219179) and in a haploid cell proliferation assay (PMID: 30209399) and disrupts binding to E2 ubiquitin conjugating enzyme (PMID: 16403807). This variant has been reported in an individual affected with breast cancer (PMID: 25186627). A different variant occurring at the same position, p.His41Arg, is classified as Pathogenic (Clinvar variation ID: 54166), suggesting that histidine at this position is important for BRCA1 function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
Variant summary: BRCA1 c.122A>T (p.His41Leu) results in a non-conservative amino acid change in 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 250784 control chromosomes. c.122A>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Tung_2014, Herzog_2021). These data indicate that the variant is likely to be associated with disease. At least one functional study reports experimental evidence evaluating an impact on protein function and showed a damaging effect of this variant on homology directed repair (HDR) activity (e.g. Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. Other variants impacting the same codon have been classified as pathogenic by our lab (p.His41Arg). Seven 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 (5 likely pathogenic/pathogenic, 2 VUS). Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 41 of the BRCA1 protein (p.His41Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 230862). 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: 25823446, 30209399, 30219179). This variant disrupts the p.His41 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20103620, 21725363, 24489791, 25823446, 30209399). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1Uncertain:1
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
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BRCA1-related cancer predisposition Pathogenic:1
The c.122A>T variant in BRCA1 is a missense variant predicted to cause substitution of histidine by leucine at amino acid 41 (p.(His41Leu)). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.56, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.00 predicts no impact on splicing (score threshold ≤0.1). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMID: 30209399, 35659930). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.78 (based on family history), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31853058). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PP3, PS3, PM2_Supporting). -
Fanconi anemia, complementation group S Pathogenic:1
This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 25186627, 30209399] -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at