17-43071046-G-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_007294.4(BRCA1):c.4868C>G(p.Ala1623Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251384Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135862
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461868Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727234
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4Uncertain:1
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not provided Pathogenic:4
The variant has been reported in individuals with hereditary breast and/or ovarian cancer in the published literature (PMID: 31869745 (2020), 29446198 (2018), 23210696 (2012), and 12491499 (2003)). In addition, this variant has been shown to aberrantly affect splicing leading to a truncated protein (PMID: 27273131 (2016) and 20513136 (2010)) and is described as a deleterious variant in a multi-factorial study (PMID 17924331 (2007)). Based on the available information, this variant is classified as pathogenic. -
PP1, PP3, PP4_strong -
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Observed in individuals with personal or family history of BRCA1-related cancers, segregating with disease in at least one family (Adem 2003, Evans 2008, Alsop 2012, Chiang 2012, Senter 2014, Plaskocinska 2016, Delgado-Balderas 2018); Published studies demonstrate a damaging effect on splicing: results in a deletion of 119 nucleotides leading to a frameshift (Walker 2010, Byers 2016, Wai 2020); Multifactorial studies report 31:1 odds in favor of causality (Easton 2007); Not observed at a significant frequency in large population cohorts (Lek 2016); While protein-based in silico analysis supports that this missense variant does not alter protein structure/function, splice predictors support a deleterious effect; Also known as 4987C>G; This variant is associated with the following publications: (PMID: 12491499, 25782689, 20513136, 30646163, 29922827, 30212499, 17924331, 22711857, 23210696, 26913838, 27273131, 26681312, 18312450, 23725378, 26052229, 20167696, 28781887, 27208206, 29997359, 29936257, 28726806, 28152038, 29446198, 30322717, 30765603, 31911673, 32123317, 31409081, 31447099, 32322110, 33087888) -
Hereditary breast ovarian cancer syndrome Pathogenic:4
This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1623 of the BRCA1 protein (p.Ala1623Gly). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs80356862, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12491499, 18312450, 22711857, 23210696, 26681312, 27208206, 29997359). ClinVar contains an entry for this variant (Variation ID: 37614). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. Studies have shown that this missense change results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 20513136, 27273131, 32123317; internal data). For these reasons, this variant has been classified as Pathogenic. -
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The p.Ala1623Gly variant in BRCA1 has been reported in >10 individuals with BRCA 1-associated cancers (Adem 2003, Easton 2007, Evans 2008, Walker 2010, Alsop 201 2, Chiang 2012, Breast Cancer Information Core (BIC) database). This variant has been identified in 1/11578 Latino chromosomes by the Exome Aggregation Consorti um (ExAC, http://exac.broadinstitute.org; dbSNP rs80356862) and has been reporte d in ClinVar (Variation ID: 37614). Computational prediction tools and conservat ion analysis suggest that this variant may not impact the protein; however, RNA analysis from affected individuals show that the p.Ala1623Gly variant causes a d eletion of 119 nucleotides in a fraction of transcripts Walker 2010). In summary , although additional studies are required to fully establish its clinical signi ficance, the p.Ala1623Gly variant is likely pathogenic. ACMG/AMP Criteria applie d: PS4, PM2, PS3_Supporting. -
Variant summary: BRCA1 c.4868C>G (p.Ala1623Gly) results in a non-conservative amino acid change located in the breast cancer cluster region (BCCR) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. However, several computational tools predict a significant impact on normal splicing: four predict the variant creates a cryptic exonic 5' donor site. This prediction has been confirmed by studies using patient derived lymphocyte mRNA that has demonstrated the variant to result in a 119 bp deletion from exon 16, leading to a truncated protein (Walker 2010, Byers 2016) (ACMG PS3). The variant had an incomplete effect on splicing, as the full length product coding for the missense protein was also detected, although in a minor fraction of the transcripts (Walker 2010). The variant allele was found at a frequency of 4.0e-06 in 251384 control chromosomes (gnomAD exomes) indicating that this is a rare variant (ACMG PM2). c.4868C>G has been reported in the literature in several affected individuals from unrelated families with a history of early onset breast and/or ovarian cancer (ranging from 39-59 in our ascertainment) (example, Adem 2002, Evans 2008, Alsop 2012, Chiang 2012, Senter 2014, Susswein 2015, Byers 2016, de Jonge 2018, Rebbeck 2018, Delgado-Balderas 2018, Gallardo-Rincon 2020). Based on the population data and the number of reported patients, the prevalence of the variant in affected individuals is significantly increased (ACMG PS4). In addition, multifactorial probability models, performing systematic assessments of BRCA variants, which included analysis of personal and family history of cancer, tumor pathology, co-occurrence in trans with known deleterious mutations and co-segregation with disease in pedigrees, predicted this variant to be likely deleterious (Easton 2007); and when the spliceogenic effect of the variant was also taken into account, this variant was predicted to be clearly pathogenic (posterior probability of pathogenicity: 0.999; Vallee 2016). These data indicate that the variant is very likely to be associated with disease. An in vitro study, examining the protein level effects of this missense change, demonstrated that the missense variant had comparable activity to the wild type in a transcriptional activation assay (Woods 2016); however, since authors used the BRCA1 cDNA sequence cloned into their vectors for mutagenesis, these data only represent the protein level effects of the missense change. Therefore, in light of the strong spliceogenic effect, this finding does not reflect the overall consequence of the variant. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=4) / likely pathogenic (n=6). Therefore, the community consensus seems to be converging on a pathological outcome for this variant. This variant was previously classified conservatively as a VUS-possibly pathogenic awaiting additional co-segregation in large families and functional evidence of the altered splice variant at the protein level. Based on the evidence outlined above, and further supported by ACMG guidelines (ACMG PM2, PS3 and PS4), the variant was classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:3
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This variant causes a C>G nucleotide substitution at position 4868 in exon 15 of the BRCA1 gene, creating a new splice donor site within the exon. RNA studies have shown that this variant results in splicing at the new splice donor site, causing the out-of-frame deletion of 119 nucleotides from the 3' end of exon 15, however sequencing has also demonstrated the splicing defect to be incomplete (PMID: 20513136, 27273131). This variant has been detected in approximately 5 individuals each affected with ovarian cancer or breast cancer (PMID: 12491499, 16685647, 18312450, 22711857, 26052229, 27208206, 29997359, 31869745; Color internal data). A multifactorial analysis has reported in a combined likelihood ratio for pathogenicity of 392.46, based on segregation, tumor pathology, family history and co-occurrence with pathogenic variant (PMID: 20513136, 26913838). This variant has been identified in 1/251384 chromosomes 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. -
The c.4868C>G pathogenic mutation (also known as p.A1623G), located in coding exon 14 of the BRCA1 gene, results from a C to G substitution at nucleotide position 4868. The alanine at codon 1623 is replaced by glycine, an amino acid with similar properties. This mutation has been reported in individuals with hereditary breast and/or ovarian cancer (Walker LC et al. Hum. Mutat. 2010 Jun;31:E1484-505; Chiang HC et al. Exp. Hematol. Oncol. 2012 Oct;1:31; Alsop K et al. J. Clin. Oncol. 2012 Jul;30:2654-63; Byers H et al. Eur. J. Hum. Genet. 2016 11;24(11):1591-1597; Plaskocinska I et al. J Med Genet. 2016 10;53:655-61; Rebbeck TR et al. Hum Mutat. 2018 05;39:593-620; Gallardo-Rincón D et al. Transl Oncol. 2020 Feb;13:212-220). RT-PCR analyses in vitro and RNA analyses on patient samples have shown that this alteration aberrantly affects splicing, causing a truncated protein subject to nonsense mediated decay (Ambry internal data; Walker LC et al. Hum. Mutat. 2010 Jun;31:E1484-505; Byers H et al. Eur. J. Hum. Genet. 2016 11;24(11):1591-1597; Wai HA et al. Genet Med. 2020 06;22:1005-1014). Of note, this alteration is also designated as 4987C>G in some published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. Based on the available evidence, this alteration is classified as a pathogenic mutation. -
Malignant tumor of breast Pathogenic:1
The variant was identified in dbSNP (ID: rs80356862) “With Pathogenic allele”; Exome Aggregation Consortium database (August 8, 2016) in 1 of 121410 chromosomes (freq. 0.000008237) in the following populations: Latino in 1 of 11578 chromosomes (freq. 0.00008637), but was not seen in African, East Asian, European (Finnish), European (Non-Finnish), South Asian and Other populations, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease; ClinVar and Clinvitae database with conflicting interpretations of pathogenicity (likely pathogenic by GeneDx and Counsyl; uncertain significance by Invitae and BIC; pathogenic by Ambry Genetics); Fanconi Anemia Mutation Database (LOVD) 2X; BRCA Share UMD Mutations Database (6X as causal); BIC database (9X with unknown clinical importance); The p.Ala1623 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the creation of a 5’ splice site. However, this information is not predictive enough to assume pathogenicity. In studies using three independent measures in the assessment of previously classified VUS variants: co-occurrence in trans of a VUS with known deleterious mutations; detailed analysis, by logistic regression, of personal and family history of cancer in VUS-carrying probands; and, in a subset of probands, an analysis of co-segregation with disease in pedigrees, the variant was determined with Odds of greater than 20:1 in Favor of Causality (Easton 2007). RT-PCR analysis identified a major splicing aberration for c.4868C>G (p.Ala1623Gly), resulting in an 119bp deletion from exon 16, and creating an aberrant splice product encoding a truncated protein. This resulted in elevated levels of an alternative mRNA isoform. Both wild-type and variant allele for BRCA1 c.4868C>G (p.Ala1623Gly) was present in subject samples from the UK and Australia (Walker 2010).rnIn summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -
not specified Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at