chr17-43063936-C-T
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.5090G>A variant in BRCA1 is a missense variant predicted to cause substitution of Cysteine by Tyrosine at amino acid 1697 (p.Cys1697Tyr). 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) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.386, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. SpliceAI predictor score of 0.02 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 30209399, 38709234) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.48 (based on Family History LR=0.48), within the thresholds for supporting benign evidence (LR >0.23 & ≥0.48) (PMID:31853058). The VCEP decided to not yet include BP5_Supporting as the LR is very close to the threshold of no evidence, and the Family history model is currently being updated. The VCEP is interested in additional data that could be incorporated in the classification of this variant, please contact the submitter. 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 (PM2_Supporting, PP3, PS3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA003230/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.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | MANE Select | c.5090G>A | p.Cys1697Tyr | missense | Exon 17 of 23 | NP_009225.1 | ||
| BRCA1 | NM_001407581.1 | c.5156G>A | p.Cys1719Tyr | missense | Exon 18 of 24 | NP_001394510.1 | |||
| BRCA1 | NM_001407582.1 | c.5156G>A | p.Cys1719Tyr | missense | Exon 18 of 24 | NP_001394511.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | TSL:1 MANE Select | c.5090G>A | p.Cys1697Tyr | missense | Exon 17 of 23 | ENSP00000350283.3 | ||
| BRCA1 | ENST00000471181.7 | TSL:1 | c.5153G>A | p.Cys1718Tyr | missense | Exon 18 of 24 | ENSP00000418960.2 | ||
| BRCA1 | ENST00000470026.6 | TSL:1 | c.5090G>A | p.Cys1697Tyr | missense | Exon 17 of 23 | ENSP00000419274.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
Hereditary breast ovarian cancer syndrome Pathogenic:2
Variant summary: BRCA1 c.5090G>A (p.Cys1697Tyr) results in a non-conservative amino acid change located in the BRCT 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 251600 control chromosomes. c.5090G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Biunno_2014, Wang_2019, Abdel-Razeq_2023, Wen_2023). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of homology directed repair (HDR) activity (example Findlay_2018). The following publications have been ascertained in the context of this evaluation (PMID: 36660366, 28781887, 30209399, 29470806, 30982232, 37523182, 24729269). ClinVar contains an entry for this variant (Variation ID: 37635). Based on the evidence outlined above, the variant was classified as pathogenic.
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1697 of the BRCA1 protein (p.Cys1697Tyr). 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: 24729269, 29470806). ClinVar contains an entry for this variant (Variation ID: 37635). Advanced modeling performed at Invitae incorporating data from internal and/or published 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: 28781887, 30209399). This variant disrupts the p.Cys1697 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11157798, 11389159, 18465347). 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
Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1
BRCA1-related cancer predisposition Pathogenic:1
The c.5090G>A variant in BRCA1 is a missense variant predicted to cause substitution of Cysteine by Tyrosine at amino acid 1697 (p.Cys1697Tyr). 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) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.386, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. SpliceAI predictor score of 0.02 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 30209399, 38709234) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.48 (based on Family History LR=0.48), within the thresholds for supporting benign evidence (LR >0.23 & ≥0.48) (PMID: 31853058). The VCEP decided to not yet include BP5_Supporting as the LR is very close to the threshold of no evidence, and the Family history model is currently being updated. The VCEP is interested in additional data that could be incorporated in the classification of this variant, please contact the submitter. 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 (PM2_Supporting, PP3, PS3).
not provided Pathogenic:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5209G>A; This variant is associated with the following publications: (PMID: 18465347, 24729269, 11389159, 15133502, 21447777, 28781887, 17305420, 20516115, 32377563, 32257056, 29884841, 25348405, 24389207, 11157798, 35665744, 30209399, 16528612, 14534301, 30263132, 30765603, 30982232, 29470806)
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.C1697Y variant (also known as c.5090G>A), located in coding exon 16 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5090. The cysteine at codon 1697 is replaced by tyrosine, an amino acid with highly dissimilar properties. Both this alteration, as well as a close-match at the same codon (p.C1697R), have been reported in multiple HBOC families (Bergthorsson JT et al. J. Med. Genet. 2001 Jun;38:361-8; Biunno I et al. Fam. Cancer. 2014 Sep;13:437-44). In addition, both alterations have demonstrated abnormal protein function with respect to transactivation, protein/peptide binding, protein stability/steady-state levels, and homology-directed repair (Woods NT et al. npg Genomic Medicine. 2016: 1:16001; Vallon-Christersson J et al. Hum. Mol. Genet. 2001 Feb;10:353-60; Glover JN. Fam. Cancer. 2006;5:89-93; Williams RS et al. J. Biol. Chem. 2003 Dec;278:53007-16; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Ambry internal data). One 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). Internal structural analysis indicates that both amino acid substitutions are predicted to disrupt the protein-protein binding interface of BRCA1 (Clapperton JA et al. Nat. Struct. Mol. Biol. 2004 Jun;11:512-8; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature. 2016 08;536:285-91). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Breast and/or ovarian cancer Uncertain:1
Malignant tumor of breast Uncertain:1
The BRCA1 p.Cys1697Tyr variant was not identified in the literature nor was it identified in the Exome Variant Server, HGMD, UMD, COSMIC, LOVD or BIC databases. The p.Cys1697 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) suggest that the p.Cys1697Tyr variant may impact the protein. In addition, Domchek (2013) notes that this residue is required for BRCA1 carboxyl-terminal (BRCT) domain function in DNA repair and tumor suppression. However, this information is not predictive enough to assume pathogenicity. A different variant at this amino acid position, p.Cys1697Arg (c.5089T>C) has been reported in the literature and in the HGMD, UMD, BIC and LOVD databases. Five functional studies have demonstrated that the p.Cys1697Arg variant has an impact on protein structure or expression (Bergthorsson 2001, Lee 2010, Vallon-Christersson 2001, Williams 2003, Williams 2004) and one study showed segregation of this variant with disease in one family (Vallon-Christersson 2001), which suggests that this residue is important to BRCA1 function. However, it should be noted that these results are limited to the substitution of an amino acid (p.Cys1697Arg) that differs from the variant that was found (p.Cys1697Tyr). In summary, based on the above information, the clinical significance of this variant cannot be determined at this time. Therefore, this variant is classified as a variant of unknown significance.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at