rs80357243
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_007294.4(BRCA1):āc.5141T>Gā(p.Val1714Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 missense
NM_007294.4 missense
Scores
13
3
3
Clinical Significance
Conservation
PhyloP100: 5.76
Genes affected
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
In a domain BRCT 1 (size 94) in uniprot entity BRCA1_HUMAN there are 74 pathogenic changes around while only 17 benign (81%) in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.859
PP5
Variant 17-43063885-A-C is Pathogenic according to our data. Variant chr17-43063885-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.5141T>G | p.Val1714Gly | missense_variant | 17/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.5141T>G | p.Val1714Gly | missense_variant | 17/23 | 1 | NM_007294.4 | ENSP00000350283.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460714Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726770
GnomAD4 exome
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1
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1460714
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31
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1Uncertain:1Other:1
not provided, no classification provided | in vitro | Brotman Baty Institute, University of Washington | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Nov 25, 2004 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 14, 2022 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 02, 2024 | This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1714 of the BRCA1 protein (p.Val1714Gly). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. 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: 26344711, 29752822). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 55413). 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: 20516115, 28781887, 30209399). Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 14, 2019 | The p.Val1714Gly variant in BRCA1 has been reported in at least 3 individuals with hereditary breast and/or ovarian cancer (HBOC) and segregated with disease in 4 affected individuals from one family (Li 2018, Zhang 2015, BIC database). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 55413). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function (Lee 2010, Findlay 2018, Woods 2016); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP Criteria applied: PM2, PS3_Moderate, PP1, PP3, PS4_Supporting. - |
Breast neoplasm Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | 3DMed Clinical Laboratory Inc | May 25, 2017 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 02, 2022 | The p.V1714G variant (also known as c.5141T>G), located in coding exon 16 of the BRCA1 gene, results from a T to G substitution at nucleotide position 5141. The valine at codon 1714 is replaced by glycine, an amino acid with dissimilar properties. In one functional study, this alteration, which is located in the BRCT domain of BRCA1, was shown to have a strong effect on protein function, including decreased transcriptional activity (<30% of WT), decreased stability (4% of WT), and decreased binding activity (13% of WT) (Lee MS et al. Cancer Res. 2010 Jun;70:4880-90). Another 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). Internal structural analysis suggest that this alteration will destabilize the overall folding of the BRCT1 domain of the BRCA1 protein (internal Ambry data). In a Chinese family, this variant co-segregated with disease in 5/5 relatives with breast and/or ovarian cancer but was not seen in two relatives with thymoma (Zhang X et al. Gene. 2015 Dec;573:333-7). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;T;.;.;T;T;.;.;.;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;M;.;.;.;.;.;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;N;N;D;.;.;N;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;.;.;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D;.;.;D
Polyphen
0.030, 1.0
.;B;.;.;.;D;.;.;.;D;.
Vest4
MVP
MPC
0.51
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at