rs386134270
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2834_2836delGTAinsC(p.Ser945ThrfsTer6) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_007294.4 frameshift, missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5
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Variant allele predicted to encode a truncated non-functional protein. -
Hereditary breast ovarian cancer syndrome Pathogenic:4
This sequence change creates a premature translational stop signal (p.Ser945Thrfs*6) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer from the French-Canadian population (PMID: 8933332, 16905680, 21324516, 23621881, 25884701). This variant is also known as 2953del3+C and 2953delGTAinsC. ClinVar contains an entry for this variant (Variation ID: 54694). For these reasons, this variant has been classified as Pathogenic. -
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Variant summary: BRCA1 c.2834_2836delinsC (p.Ser945ThrfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251290 control chromosomes (gnomAD). c.2834_2836delinsC has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Durocher_1996, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Eight ClinVar submitters including an expert panel (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
The c.2834_2836delGTAinsC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from the deletion of 3 nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.S945Tfs*6). This alteration has been recognized as a founder mutation in the French Canadian population, having been identified in multiple individuals and families of French Canadian descent with hereditary breast and/or ovarian cancer (Durocher F et al. J Med Genet 1996 Oct;33(10):814-9; Tonin PN et al. Am J Hum Genet, 1998 Nov;63:1341-51; Oros KK et al. Int. J. Cancer 2004 Nov;112(3):411-9; Ghadirian P et al. Clin Genet 2014 Jan;85(1):31-5; Belanger MH et al. J Ovarian Res 2015;8(1):1). Of note, this alteration is also designated as 2953delGTAinsC in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
This variant replaces 3 nucleotides in exon 10 of the BRCA1 gene with 1 new nucleotide, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with breast and/or ovarian cancer, and is common in the French-Canadian population (PMID: 8933332, 9792861, 10686936, 15382066, 16905680, 21324516, 23621881, 24333842, 25884701). This variant has been identified in 24 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). In a large breast cancer case-control study, this variant has been observed in 0/60466 cases and 1/53460 controls (PMID: 33471991). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Breast and/or ovarian cancer Pathogenic:1
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not provided Pathogenic:1
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Identified in patients with a personal or family history consistent with pathogenic variants in this gene, and is common in the French Canadian population (Durocher 1996, Tonin 1998, Oros 2004, Simard 2007, Ghadirian 2014); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2953_2955delGTAinsC; This variant is associated with the following publications: (PMID: 21947752, 8933332, 21324516, 25884701, 15382066, 16905680, 23621881, 9792861, 10422801, 23302520, 24950059, 26941049, 29907814, 30322717, 32300229, 32719484) -
Malignant tumor of breast Pathogenic:1
The BRCA1 p.Ser945ThrfsX6 variant was identified in 13 of 3714 proband chromosomes (frequency: 0.004) from individuals of French Canadian families with ovarian and breast cancer (Durocher 1996, Feilotter 2014, Letourneau 2012, Oros 2004, Simard 2007, Zhang 2011), however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified by our laboratory in 8 individuals with ovarian and breast cancer. The variant was also identified in the ClinVar database (classified as a Pathogenic variant by the Sharing Clinical Reports Project, derived from Myriad reports), the BIC database (9X with clinical importance), and UMD (1X as a causal variant).The p.Ser945ThrfsX6 deletion/insertion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 945 and leads to a premature stop codon 6 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at