17-43094309-T-C
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_007294.4(BRCA1):c.1222A>G(p.Lys408Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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 -5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250812Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135548
GnomAD4 exome AF: 0.0000280 AC: 41AN: 1461860Hom.: 0 Cov.: 34 AF XY: 0.0000248 AC XY: 18AN XY: 727228
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:1
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Hereditary cancer-predisposing syndrome Benign:3
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
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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. -
not provided Uncertain:2
The BRCA1 c.1222A>G (p.Lys408Glu) variant has been reported in the published literature in healthy individuals and individuals with breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA1)). Additionally, this variant is reported to be located in a region of BRCA1 that is tolerant to missense sequence changes ((PMID: 31911673 (2020)), as well as being located near phosphorylated residues (PMID: 25722345 (2015), 23704879 (2013)). The frequency of this variant in the general population, 0.000004 (1/250812 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Variant summary: The BRCA1 c.1222A>G (p.Lys408Glu) variant involves the alteration of a non-conserved nucleotide. 3/3 in silico tools predict a benign outcome for this variant (SNPs&GO and MutationTaster not captured due to low reliability index). This variant is absent in 121218 control chromosomes. Clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign, without evidence to independently evaluate. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -
BRCA1-related disorder Uncertain:1
The BRCA1 c.1222A>G variant is predicted to result in the amino acid substitution p.Lys408Glu. This variant has been reported in an individual undergoing testing for breast/ovarian cancer but was considered likely benign due to the Lys408 residue being a glutamic acid (Glu) in several other species (Abkevich et al. 2004. PubMed ID: 15235020). This variant occurs within a region of the BRCA1 gene that is predicted to be tolerant to missense variation (Table 2, Dines et al. 2020. PubMed ID: 31911673). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/37399/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
not specified Benign:1
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Malignant tumor of breast Benign:1
The BRCA1 p.Lys408Glu variant was identified in the literature however the frequency of this variant in an affected population was not provided. Ther variant was reported in a study using computation analysis to classify variant as was determined to be neutral (Abkevich 2004). The variant was also identified in dbSNP (ID: rs80357253) as “With Pathogenic, other allele” as a separate variant is reported to cause a nonsense change at this loci. The variants was also identified in ClinVar (as uncertain significance by Lab Corp, BIC; likely benign by Ambry Genetics, GeneDx and Invitae and benign by Sharing Clinical Reports Project), and LOVD 3.0 (5x predicted neutral). The variant was identified in control databases in 1 of 245604 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 1 of 111140 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, EastAsian, Finnish, and South Asian populations. The p.Lys408Glu residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Hereditary breast ovarian cancer syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at