17-43093408-G-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6
The NM_007294.4(BRCA1):c.2123C>A(p.Ser708Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000677 AC: 17AN: 251170Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135762
GnomAD4 exome AF: 0.0000383 AC: 56AN: 1461790Hom.: 0 Cov.: 41 AF XY: 0.0000591 AC XY: 43AN XY: 727192
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74302
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:5
PP4, BS1, BS3, BP1_Strong c.2123C>A, located in exon 10 (11 according BIC nomenclature) of the BRCA1 gene, is predicted to result in the substitution of serine by tyrosine at codon 708, p.(Ser708Tyr). This position is outside a (potentially) clinically important functional domain and, moreover, the SpliceAI algorithm predicts no significant impact on splicing (BP1_strong). The variant allele was found in 12/30518 alleles, with a filter allele frequency of 0.0178% at 99% confidence, within the South Asian population in the gnomAD v2.1.1 database (non-cancer data set) (BS1). BRCA1 c.2123C>A was reported by one calibrated study to affect protein function similar to benign control variants (PMID: 32546644) (BS3). Published clinical data for a multifactorial likelihood analysis (PMID: 31131967) showed a combined LR indicative of supporting evidence towards pathogenicity (LR 3.73), based on tumour characteristics (LR 3.73) (PP4). In addition, the variant was also identified in the following databases: BRCA Exchange (Not Yet Reviewed), ClinVar (2x benign, 8x likely benign, 4x uncertain significance) and LOVD (2x likely benign, 6x uncertain significance). Based on the currently available information, c.2123C>A is classified as a benign variant according to ClinGen-BRCA1 Guidelines version v1.0.0. -
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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. -
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:2
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PP4(Supporting)+BS1(Strong)+BS3(Strong)+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) -
not provided Uncertain:2
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Also known as 2242C>A; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12531920, 15385441, 16267036, 26689913, 27062684, 31131967, 20858050, 28529006, 31409081, 32546644, 32377563, 15343273, 29884841, 35402282) -
not specified Benign:2
Variant summary: BRCA1 c.2123C>A (p.Ser708Tyr) 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. The variant allele was found at a frequency of 6.8e-05 in 251170 control chromosomes, predominantly at a frequency of 0.00039 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (6.8e-05 vs 0.001), allowing no conclusion about variant significance. c.2123C>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (example, Judkins_2005, Coulet_2010, Azzollini_2016). At-least one report of this variant co-occurring with a pathogenic variant (c.2062C>T, p.Gln688*) in the PTCH1 gene as an alternate molecular basis of disease in an individual with Gorlin syndrome has been reported (Paulo_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least two publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein had comparable homology-directed repair (HDR) activity to the wild type (Lu_2015) and a neutral impact in homologous recombination repair complementation assays (Bouwman_2020). Seven ClinVar submissons from clinical diagnostic laboratories (evaluation after 2014) cites the variant four times as uncertain significance and thrice as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
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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). -
Hereditary breast ovarian cancer syndrome Benign:1
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Fanconi anemia, complementation group S Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at