rs769535925
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_000059.4(BRCA2):āc.4320A>Cā(p.Lys1440Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,443,244 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1440E) has been classified as Uncertain significance.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.4320A>C | p.Lys1440Asn | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.4320A>C | p.Lys1440Asn | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.0000165 AC: 4AN: 242172Hom.: 0 AF XY: 0.0000228 AC XY: 3AN XY: 131332
GnomAD4 exome AF: 0.00000346 AC: 5AN: 1443244Hom.: 0 Cov.: 35 AF XY: 0.00000560 AC XY: 4AN XY: 714692
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 16, 2023 | The p.K1440N variant (also known as c.4320A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 4320. The lysine at codon 1440 is replaced by asparagine, an amino acid with similar properties. This alteration was observed with an allele frequency of 0.00014 unselected breast cancer patients and with an allele frequency of 0.00018 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083). This alteration has also been identified in multiple Korean individuals diagnosed with breast cancer (Seong MW et al. Clin Genet, 2009 Aug;76:152-60; Park KS et al. Genet. Med. 2016 12;18:1250-1257; Kim HN et al. Chonnam Med J, 2019 May;55:99-103). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
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). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 11, 2023 | This missense variant replaces lysine with asparagine at codon 1440 in the RAD51 binding domain of the BRCA2 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 breast, pancreatic and prostate cancer case-control studies in which this variant was detected in 1 cancer case and up to 5 unaffected individuals in each study (PMID: 19656164, 30287823, 31214711, 32980694) and this variant has also been detected in the general population in 4/242172 chromosomes 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. - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 16, 2019 | Variant summary: BRCA2 c.4320A>C (p.Lys1440Asn) results in a non-conservative amino acid change in the encoded protein sequence, located in the third BRCA2 repeat domain, which is conserved and is involved in binding to Rad51 (IPR002093). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7-05 in 242172 control chromosomes, exclusively observed within the Korean subpopulation with a frequency of 0.00022 (4/3818) in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.4320A>C, has been reported in the literature in Korean individuals affected with breast cancer (Seong_2009, Park_2017). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 02, 2023 | This missense variant replaces lysine with asparagine at codon 1440 in the RAD51 binding domain of the BRCA2 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 breast, pancreatic and prostate cancer case-control studies in which this variant was detected in 1 cancer case and up to 5 unaffected individuals in each study (PMID: 19656164, 30287823, 31214711, 32980694) and this variant has also been detected in the general population in 4/242172 chromosomes 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 13, 2021 | Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 4548A>C; This variant is associated with the following publications: (PMID: 30287823, 19656164, 30415210, 28111427, 27124784, 22193408, 9002670, 31825140) - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1440 of the BRCA2 protein (p.Lys1440Asn). This variant is present in population databases (rs769535925, gnomAD 0.02%). This missense change has been observed in individual(s) with BRCA2-related conditions (PMID: 19656164, 27124784, 31907386). ClinVar contains an entry for this variant (Variation ID: 418974). 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 BRCA2 protein function with a negative predictive value of 95%. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at