ClinVar Genomic variation as it relates to human health

In the published literature, the variant was identified in an individual affected with sporadic breast cancer (PMID: 21918853 (2012)) and in a family suspected of having hereditary breast/ovarian cancer (PMID: 29061375 (2018)). The variant was also reported in an individual with osteosarcoma (PMID: 26580448 (2015)). The frequency of this variant in the general population, 0.00032 (8/24908 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.

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.

The BRCA2 c.9052_9057del6 variant is predicted to result in an in-frame deletion (p.Lys3019_Ser3020del). This variant is also known as c.9280_9285del (p.3014_3015delSK), has been reported in individuals with breast and/or ovarian cancer (de Juan Jiménez et al. 2012. PubMed ID: 21918853; Capone et al. 2017. PubMed ID: 29061375. Table S1). This variant is reported in 0.032% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32953980-CTAAAAG-C). In ClinVar, this variant has conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/185294/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

This variant results in an in-frame deletion of two amino acids in the BRCA2 protein. This variant is also known as 9280_9285del and p.3014_3015delSK in the literature. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individuals affected with a personal or family history of breast cancer (PMID: 21918853, 35753294). This variant has been identified in 10/281852 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.

The BRCA2 c.9052_9057del; p.Lys3019_Ser3020del variant (rs786202063), also published as c.9280_9285del; p.3014_3015delSK, is reported in the literature in an individual affected with breast cancer, although its clinical significance was uncertain (de Juan Jimenez 2012). This variant is also reported in ClinVar (Variation ID: 185294). It is found on ten chromosomes (10/281852 alleles) in the Genome Aggregation Database. This variant deletes two amino acids, leaving the rest of the protein in-frame. Due to limited information, the clinical significance of the p.Lys3019_Ser3020del variant is uncertain at this time. References: de Juan Jimenez I et al. Low prevalence of BRCA1 and BRCA2 mutations in the sporadic breast cancer of Spanish population. Fam Cancer. 2012 Mar;11(1):49-56. PMID: 21918853.

This variant, c.9052_9057del, results in the deletion of 2 amino acid(s) of the BRCA2 protein (p.Lys3019_Ser3020del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs763756705, gnomAD 0.03%). This variant has been observed in individual(s) with BRCA2-related cancers (PMID: 21918853, 26580448). This variant is also known as c.9280_9285del (p.3014_3015delSK) or S3018_K3019del. ClinVar contains an entry for this variant (Variation ID: 185294). 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.

Variant summary: BRCA2 c.9052_9057delAGTAAA (p.Lys3019_Ser3020del) results in an in-frame deletion that is predicted to remove two amino acids from the encoded protein. The variant allele was found at a frequency of 2.8e-05 in 250472 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9052_9057delAGTAAA has been reported in the literature in individuals affected with breast cancer (e.g., deJuanJimenez_2021), individuals with a personal or family history of BRCA-related cancer (e.g., Houdayer_2012, Bisgin_2022, Capone_2018), and in a pediatric osteosarcoma case (e.g., Zhang_2015), however without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Additionally, 4/4 computational tools predict no significant impact on normal splicing, and these predictions are supported by a functional study that found the variant had no effect on splicing at the cDNA level (e.g., Houdayer_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35753294, 29061375, 22505045, 28243543, 26580448, 21918853). ClinVar contains an entry for this variant (Variation ID: 185294). Based on the evidence outlined above, the variant was classified as uncertain significance.

Observed in individuals with a personal and/or family history of BRCA2-related cancers and in a pediatric patient with osteosarcoma (PMID: 21918853, 26580448, 29061375, 38069422); In silico analysis supports a deleterious effect on protein structure/function; In-framed deletion of 2 amino acids in a repetitive region; Also known as 9280_9285delAGTAAA; This variant is associated with the following publications: (PMID: 26580448, 21918853, 28243543, 31131967, 29061375, 31853058, 38069422, 12228710, 37216690)