17-43104258-G-C
Position:
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. BP1_StrongBS3BP5_StrongPM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.305C>G variant in BRCA1 is a missense variant predicted to cause substitution of Alanine by Glycine at amino acid 102 (p.Ala102Gly). 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 missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.00, score threshold <0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID:30219179) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.015 (based on Co-occurrence LR=1.177; Family History LR=0.0127), below the threshold for strong benign evidence (LR <0.05) (BP5_Strong met; PMID:31131967, 31853058). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, BP1_Strong, BS3, BP5_Strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA002009/MONDO:0011450/092
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
BRCA1
ENST00000357654.9 missense
ENST00000357654.9 missense
Scores
2
6
11
Clinical Significance
Conservation
PhyloP100: 1.52
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 Benign. Variant got -11 ACMG points.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
BP1
For more information check the summary or visit ClinGen Evidence Repository.
BP5
For more information check the summary or visit ClinGen Evidence Repository.
BS3
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.305C>G | p.Ala102Gly | missense_variant | 6/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.305C>G | p.Ala102Gly | missense_variant | 6/23 | 1 | NM_007294.4 | ENSP00000350283.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000275 AC: 4AN: 1457078Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2AN XY: 725154
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33
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GnomAD4 genome
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32
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ClinVar
Significance: Benign
Submissions summary: Uncertain:4Benign:7
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 21, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 15, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 24, 2024 | The p.A102G variant (also known as c.305C>G), located in coding exon 5 of the BRCA1 gene, results from a C to G substitution at nucleotide position 305. The alanine at codon 102 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in conjunction with a pathogenic gross deletion in BRCA1 in a hereditary breast and ovarian cancer family (Palma MD et al. Cancer Res. 2008 Sep 1;68(17):7006-14). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 07, 2023 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Nov 25, 2004 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jul 17, 2012 | - - |
not provided Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 03, 2019 | This variant is associated with the following publications: (PMID: 18703817, 25814778, 22711857) - |
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
not specified Benign:1
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 13, 2021 | Variant summary: The variant, BRCA1 c.305C>G (p.Ala102Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as benign (IARC class 1) in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019, Cline_2019). The variant was absent in 250608 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.305C>G has been reported in the literature in individuals affected with Breast cancer and ovarian cancer (Alsop_2012, Palma_2008). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Recently a large scale multifactorial likelihood quantitative analysis approach based on variant location, bioinformatic prediction of variant effect, cosegregation, family cancer history profile, cooccurrence with a pathogenic variant in the same gene, breast tumor pathology, and casecontrol information has classified this variant as benign (Parsons_2019). At-least one co-occurrence with another pathogenic variants have been reported (BRCA1 Del exons 8-9, Palma_2008 and an unspecified co-occurrence in Alsop_2012), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as benign (n=1, including the expert panel)/likely benign (n=3). Based on the evidence outlined above, the variant was re-classified as Benign. - |
BRCA1-related cancer predisposition Benign:1
| Benign, reviewed by expert panel | curation | ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen | Jun 11, 2024 | The c.305C>G variant in BRCA1 is a missense variant predicted to cause substitution of Alanine by Glycine at amino acid 102 (p.Ala102Gly). 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 missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.00, score threshold <0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 30219179) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.015 (based on Co-occurrence LR=1.177; Family History LR=0.0127), below the threshold for strong benign evidence (LR <0.05) (BP5_Strong met; PMID: 31131967, 31853058). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, BP1_Strong, BS3, BP5_Strong). - |
Hereditary breast ovarian cancer syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;N;N;.
REVEL
Uncertain
Sift
Benign
T;D;D;T;D;D;D;D;D;D;D;.;D;D;D;T;D;.
Sift4G
Benign
T;D;D;T;T;T;.;.;T;.;D;.;T;.;T;.;.;.
Polyphen
0.057, 0.78, 0.092
.;B;.;.;.;P;.;.;.;.;B;.;.;.;.;.;.;.
Vest4
MutPred
Loss of stability (P = 0.0442);Loss of stability (P = 0.0442);Loss of stability (P = 0.0442);Loss of stability (P = 0.0442);.;Loss of stability (P = 0.0442);.;Loss of stability (P = 0.0442);.;.;Loss of stability (P = 0.0442);Loss of stability (P = 0.0442);Loss of stability (P = 0.0442);.;Loss of stability (P = 0.0442);Loss of stability (P = 0.0442);.;.;
MVP
MPC
0.18
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
Find out detailed SpliceAI scores and Pangolin per-transcript scores at