ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4037C>A (p.Thr1346Asn)

dbSNP: rs1555283519
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000637490 SCV000758951 uncertain significance Hereditary breast ovarian cancer syndrome 2024-10-07 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1346 of the BRCA2 protein (p.Thr1346Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 31825140). ClinVar contains an entry for this variant (Variation ID: 433781). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Sema4, Sema4 RCV002256321 SCV002533840 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-18 criteria provided, single submitter curation
University of Washington Department of Laboratory Medicine, University of Washington RCV002256321 SCV003848628 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
GeneDx RCV004760535 SCV005371057 uncertain significance not provided 2024-04-05 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 4265C>A; This variant is associated with the following publications: (PMID: 31825140, 32467295)
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000500883 SCV000591884 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The p.Thr1346Asn variant was not identified in the literature nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, COSMIC, UMD, ClinVar, or BIC databases. The p.Thr1346 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the clinical significance of this variant and this information is not predictive enough to rule out pathogenicity. In addition, 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. This variant is classified as a variant of unknown significance.

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