rs80358402
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PVS1_ModerateBP6_Very_Strong
The NM_000059.4(BRCA2):c.10222A>T(p.Lys3408Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. K3408K) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.10222A>T | p.Lys3408Ter | stop_gained | 27/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.10222A>T | p.Lys3408Ter | stop_gained | 27/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251000Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135680
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461720Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 727160
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74368
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:2
Benign, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Lys3408X variant was not identified in the literature but was identified in the BIC database (1X with no clinical importance), dbSNP (ID: rs80358402), and in the ClinVar database (classified as likely benign by GeneDx and Ambry Genetics; classified as benign by BIC; classification not provided by Invitae). The variant was listed in the Exome Aggregation Consortium (ExAC) database in 1 of 65858 chromosomes (frequency: 0.00002) from a population of European (Non-Finnish) individuals; however, this single observation and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant results in termination of translation at amino acid position 3408 and the loss of the terminal 9 amino acids of the expressed BRCA2 protein. Borg (2010) identified three variants in the BRCA2 gene near the 3’-end which were predicted to result in protein truncation (c.9976A>T (BIC: K3326X), c.10095delCins11 (BIC: 10323delCins11), c.10150C>T (BIC: R3384X), but were “ruled as exceptions that could not be classified because of their location near the 3’-end and possibly dispensable part of the gene”. The p.Lys3408X variant is located even farther downstream than these variants (i.e. closer to the 3’- end of the gene). Stop codon or nonsense mutations in the last exon of a gene may not be subjected to nonsense mediated RNA decay, although further study would be required to validate this hypothesis and it is currently not possible to determine whether or not this might influence the severity of the disorder. Segregation and/or functional studies are recommended to further elucidate the pathogenicity of this variant. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Apr 05, 2017 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 25, 2022 | See Variant Classification Assertion Criteria. - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 17, 2023 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 12, 2019 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 22, 2017 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 13, 2023 | Variant summary: BRCA2 c.10222A>T (p.Lys3408X) results in a premature termination codon, predicted to cause a truncation of the encoded protein by 10 amino acids and is not expected to undergo NMD. The variant allele was found at a frequency of 2.6e-05 in 152220 control chromosomes, and was also found in a woman >70 years of age who has never had cancer (FLOSSIES). The BRCA2 c.9976A>T (p.Lys3326*) variant, located upstream of this variant and also in the last exon of the gene, is a known benign variant suggesting that the truncation of the last 93 amino acids of BRCA2 is unlikely to be pathogenic for breast and/or ovarian cancer. c.10222A>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome without evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign Based on the evidence outlined above, the variant was classified as likely benign. - |
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at