17-43076488-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM5PP5_Very_Strong
The NM_007294.4(BRCA1):c.4484G>A(p.Arg1495Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1495M) has been classified as Pathogenic.
Frequency
Consequence
NM_007294.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:6Uncertain:1
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not provided Pathogenic:2Uncertain:2
RNA analyses demonstrate that this variant leads to skipping of exon 14, resulting in premature protein truncation, subject to nonsense-mediated decay (Houdayer et al., 2012; Wangensteen et al., 2019); Observed in individuals with breast and/or ovarian cancer (Alsop et al., 2012, George et al., 2013, Fernandes et al., 2016, Turner et al., 2018, Slavin et al., 2019); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 4603G>A; This variant is associated with the following publications: (PMID: 22711857, 27741520, 28888541, 22762150, 19471317, 23633455, 22045683, 21523855, 15280182, 16267036, 28637432, 29339979, 28781887, 30728895, 29875428, 29446198, 30765603, 31143303, 31131967, 31911673, 31124283, Tan2020[Abstract], Lertwilaiwittaya2020[Case Report], 34981296, 35918668, 35665744, 15343273, 22737296, 22505045) -
The variant occurs at the last base of an exon and interferes with normal BRCA1 mRNA splicing. 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 affected with breast/ovarian cancer (PMID: 22711857 (2012), 23633455 (2013), 27741520 (2016), 28637432 (2017), 29875428 (2018), 34196900 (2021)). In vitro studies have shown that this variant causes a severe and complete splicing defect resulting in exon 13 (legacy exon 14) skipping (PMID: 19471317 (2009), 22505045 (2012), 31143303 (2019)). Based on the available information, this variant is classified as pathogenic. -
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Hereditary cancer-predisposing syndrome Pathogenic:2
This missense variant replaces arginine with lysine at codon 1495 of the BRCA1 protein and alters the conserved guanine nucleotide immediately adjacent to the intron 13 splice donor site. RNA studies have shown that this variant resulted in the out-of-frame skipping of exon 13 and that this variant transcript is not stably expressed based on an allelic imbalance assay on patient-derived RNA (PMID: 19471317, 22505045, 31143303). This variant has been reported in at least three individuals affected with breast and ovarian cancer (PMID: 22711857, 27741520, 28637432) and also in suspected hereditary breast and ovarian cancer families (PMID: 22505045, 22762150). Two similar variants at this nucleotide position, c.4484G>T and c.4484G>C, have been reported in individuals and families affected with breast and ovarian cancer (PMID: 10571952, 21120943, 22762150, 24607278, 27425403) and shown by RNA analysis to cause out-of-frame skipping of exon 13 (PMID: 10571952, 12915465, 21120943, 22505045, 24607278). 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. -
The c.4484G>A pathogenic mutation (also known as p.R1495K), located in coding exon 12 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4484. The amino acid change results in arginine to lysine at codon 1495, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. RNA studies demonstrated that this mutation leads to skipping of coding exon 12, which results in a transcript subject to nonsense-mediated mRNA decay (Ambry internal data; Houdayer C et al. Hum Mutat. 2012 Aug;33(8):1228-38). Another alteration impacting the same donor/acceptor site (c.4484G>T) has been shown to have a similar impact on splicing (Ambry internal data; Yang Y et al. Hum. Mol. Genet. 2003 Sep;12:2121-31; Caux-Moncoutier V et al. Hum. Mutat. 2011 Mar;32:325-34; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38). This nucleotide 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 silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
Variant summary: BRCA1 c.4484G>A (p.Arg1495Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a canonical 5' splicing donor site and two predict the variant weakens the 5' donor site. At least two publications have provided experimental evidence to demonstrate that this variant does indeed affect mRNA splicing, indicating that it results in the skipping of exon 13 which produces a frameshift, ultimately leading to a premature stop codon (e.g. Houdayer_2012, Wangensteen_2019). The variant was absent in 251172 control chromosomes (gnomAD). c.4484G>A has been reported in the literature in multiple individuals affected with breast/ovarian cancer, including those with a family history of breast/ovarian cancer (e.g. Lecarpentier_2012, Alsop_2012, Fernandes_2016, Turner_2019, Ren_2021, Solano_2021). These data strongly suggest that the variant is associated with disease. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic (n=6) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1495 of the BRCA1 protein (p.Arg1495Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 22711857, 22762150, 23633455, 27741520, 29446198). ClinVar contains an entry for this variant (Variation ID: 37597). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 13 (also called exon 14 in published literature), and produces a non-functional protein and/or introduces a premature termination codon (PMID: 19471317, 22505045; internal data). This variant disrupts the c.4484G nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (internal data). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Familial cancer of breast Pathogenic:1
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Malignant tumor of breast Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at