chr17-43094642-T-G
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PVS1PM2BP6
The ENST00000497488.2(BRCA1):āc.1A>Cā(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
BRCA1
ENST00000497488.2 start_lost
ENST00000497488.2 start_lost
Scores
7
12
Clinical Significance
Conservation
PhyloP100: 1.01
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 Likely_pathogenic. Variant got 9 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 17-43094642-T-G is Benign according to our data. Variant chr17-43094642-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55741.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.889A>C | p.Met297Leu | missense_variant | 10/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.889A>C | p.Met297Leu | missense_variant | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461874Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727236
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1
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1461874
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34
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0
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727236
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
Bravo
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Medical and Surgical Sciences, University of Bologna | Sep 01, 2023 | PM2(Supporting)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 03, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 12, 2023 | The p.M297L variant (also known as c.889A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 889. The methionine at codon 297 is replaced by leucine, an amino acid with highly similar properties. This alteration was reported in trans with a BRCA1 pathogenic mutation based on haplotype analysis in a patient with breast and/or ovarian cancer who underwent clinical genetic testing, and was classified as a variant of unknown significance (Judkins T et al. Cancer Res. 2005 Nov;65(21):10096-103). In a study of 1854 high-risk breast/ovarian cancer families in Italy, this alteration was detected in one family (Azzollini J et al. Eur. J. Intern. Med., 2016 Jul;32:65-71). This alteration was also observed in 1 of 1045 Italian patients with breast and/or ovarian cancer fulfilling established criteria for HBOC genetic testing (Zuntini R et al. Front Genet, 2018 Sep;9:378). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 07, 2022 | This missense variant replaces methionine with leucine at codon 297 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual affected with breast cancer and one suspected hereditary breast and ovarian cancer family (PMID: 27062684, 30254663, 32380732, 34178674). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Likely benign, criteria provided, single submitter | curation | University of Washington Department of Laboratory Medicine, University of Washington | Mar 23, 2023 | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 26, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 1008A>C; Observed in individuals with breast and/or ovarian cancer (Azzollini et al., 2016; Zuntini et al., 2018; Fanale et al., 2021); This variant is associated with the following publications: (PMID: 31131967, 27062684, 16267036, 15235020, 34178674, 30254663, 20215511, 15343273, 9788437, 9926942, 9582019) - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 23, 2023 | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 55741). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 15235020, 27062684, 30254663, 34178674). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 297 of the BRCA1 protein (p.Met297Leu). - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency | Apr 18, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;.;.;T;T;.;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T;T;T;T;D;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;.;N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T;.;T;T;T;T
Sift4G
Benign
T;T;T;T;.;T;.;T;T
Polyphen
B;.;.;B;.;.;.;.;.
Vest4
MutPred
Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);.;Gain of helix (P = 0.0325);.;Gain of helix (P = 0.0325);.;.;Gain of helix (P = 0.0325);
MVP
MPC
0.077
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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