ClinVar Genomic variation as it relates to human health

Variant summary: BRCA2 c.44_45insATT (p.Ile14_Phe15insLeu) results in an in-frame insertion that is predicted to insert one amino acid into the encoded protein. The variant allele was found at a frequency of 4e-06 in 251358 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.44_45insATT has been reported in the literature in at least one individual affected with Ovarian Cancer. This report does 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. Five 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

The frequency of this variant in the general population, 0.000004 (1/251358 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with ovarian cancer (PMID: 32483276 (2020)). Based on the available information, we are unable to determine the clinical significance of this variant.

This variant causes an in-frame insertion of 1 amino acid in exon 2 of the BRCA2 gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251358 chromosomes in the general population 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.

This variant, c.44_45insATT, results in the insertion of 1 amino acid(s) of the BRCA2 protein (p.Ile14_Phe15insLeu), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs766906962, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 125984). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.

The c.44_45insATT variant (also known as p.I14_F15insL), located in coding exon 1 of the BRCA2 gene, results from an in-frame ATT insertion at nucleotide positions 44 to 45. This results in the insertion of an extra leucine residue between codons 14 and 15. This amino acid region is well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear.

In-frame insertion of 1 amino acid in a non-repeat region; In silico analysis indicates that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 272_273insATT, 272insATT and L15ins; This variant is associated with the following publications: (PMID: 19941162, 32483276)