17-43093376-T-C
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP1_StrongBS1BP5_Strong
This summary comes from the ClinGen Evidence Repository: The c.2155A>G variant in BRCA1 is a missense variant predicted to cause substitution of Lysine by Glutamic acid at amino acid 719 (p.Lys719Glu). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.0003 in the African/African American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.0001) for BS1, and below the BA1 threshold (>0.001) (BS1 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 0.01, score threshold <0.1) (BP1_Strong met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.0000515 (based on Family History LR= 0.0000515), below the thresholds for very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: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 (BS1, BP1_Strong, BP5_Very strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA001442/MONDO:0011450/092
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000191 AC: 29AN: 152214Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 250994Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135712
GnomAD4 exome AF: 0.0000260 AC: 38AN: 1461728Hom.: 0 Cov.: 41 AF XY: 0.0000234 AC XY: 17AN XY: 727156
GnomAD4 genome AF: 0.000190 AC: 29AN: 152332Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17AN XY: 74490
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or pancreatic cancer (PMID: 26287763, 30883245); Also known as 2274A>G; This variant is associated with the following publications: (PMID: 16267036, 15385441, 28135145, 26287763, 30883245, 30603682, 15343273) -
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The BRCA1 c.2155A>G; p.Lys719Glu variant (rs80357147), is reported in the literature in at least one individual affected with breast cancer, though it was not demonstrated to be disease-causing (Pal 2015). This variant is found in the African population with an overall allele frequency of 0.08% (20/24898 alleles) in the Genome Aggregation Database, and it is reported in ClinVar (Variation ID: 37452). The lysine at codon 719 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Lys719Glu variant is uncertain at this time. References: Pal T et al. A high frequency of BRCA mutations in young black women with breast cancer residing in Florida. Cancer. 2015 Dec 1;121(23):4173-80. -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
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Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
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not specified Uncertain:2
This sequence change does not appear to have been previously described in individuals with BRCA1-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.080% in the African subpopulation (dbSNP rs80357147). The p.Lys719Glu change affects a poorly conserved amino acid residue located in a domain of the BRCA1 protein that is known to be functional. The p.Lys719Glu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Lys719Glu change remains unknown at this time. -
Variant summary: BRCA1 c.2155A>G (p.Lys719Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251194 control chromosomes, predominantly at a frequency of 0.00062 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (4.8e-05 vs 0.001), allowing no conclusion about variant significance. However, the variant was reported in 5/2559 African American women (i.e. with an allele frequency of about 0.001), who were older than age 70, and have never had cancer (in the FLOSSIES database), suggesting that the variant might be a benign polymorphism. c.2155A>G, has been reported in the literature in individuals affected with or without a family history of Breast and Ovarian Cancer (Judkins_2005, Pal_2015, Abe_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30883245, 16267036, 26287763, 15385441). Fourteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=6) and VUS (n=). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2
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BRCA1-related cancer predisposition Benign:2
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The c.2155A>G variant in BRCA1 is a missense variant predicted to cause substitution of Lysine by Glutamic acid at amino acid 719 (p.Lys719Glu). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth >=20) or gnomAD v3.1 (non-cancer subset, read depth >=20) is 0.0003 in the African/African American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.0001) for BS1, and below the BA1 threshold (>0.001) (BS1 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 0.01, score threshold <0.1) (BP1_Strong met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.0000515 (based on Family History LR= 0.0000515), below the thresholds for very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 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 (BS1, BP1_Strong, BP5_Very strong). -
Hereditary breast ovarian cancer syndrome Benign:2
The BRCA1 c.2155A>G (p.Lys719Glu) missense change has a maximum subpopulation frequency of 0.080% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/17-41245393-T-C). Seven of seven in silico tools predict a benign effect of this variant on protein function (BP4), however to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in two individuals with a family history of pancreatic cancer, one of which also had a family history of breast and colon cancer (PMID: 30883245). In addition, this variant has been reported in five women older than 70 years of age who have never had cancer (BS2_supporting; https://whi.color.com/variant/17-41245393-T-C). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS2_supporting, BP4. -
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Breast and/or ovarian cancer Uncertain:1
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BRCA1-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at