ClinVar Genomic variation as it relates to human health

Variant summary: BRCA2 c.7865A>G (p.Asn2622Ser) results in a conservative amino acid change located in the helical domain (IPR015252) of the encoded protein sequence. 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 2.8e-05 in 251260 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7865A>G has been reported in the literature in at least one individual affected with breast cancer (Tung_2014). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) have been observed at our laboratory (BRCA1 c.5324T>G, p.Met1775Arg), providing supporting evidence for a benign role. Multiple publications report conflicting experimental evidence evaluating an impact on protein function that does not allow convincing conclusions about the variant effect. Specifically, some studies through the performance of HDR assays and the MANO-B method (which utilizes BRCA2-deficient cells and PARP inhibitors), determined the variant to be damaging/abnormal (Hart_2019, Ikegami_2020, Richardson_2021). However, a different study utilizing a mouse embryonic stem cell (mESC)-based assay to examine the ability to rescue the lethality of Brca2 null mESC as well as sensitivity to six DNA damaging agents, determined the variant to be functional (Biswas_2020). The following publications have been ascertained in the context of this evaluation (PMID: 33293522, 29884841, 32444794, 33609447, 25186627). ClinVar contains an entry for this variant (Variation ID: 91496). Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.N2622S variant (also known as c.7865A>G), located in coding exon 16 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7865. The asparagine at codon 2622 is replaced by serine, an amino acid with highly similar properties. This alteration was reported in a woman with breast cancer diagnosed under age 50 from a cohort of 2158 women who underwent multi-gene panel testing for hereditary breast cancer (Tung N et al. Cancer. 2015 Jan;121(1):25-33). This variant was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This variant was non-functional in a homology-directed DNA repair (HDR) assay (Hart SN et al. Genet. Med. 2018 Jun;21(1):71-80; Richardson ME et al. Am J Hum Genet, 2021 03;108:458-468). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.

Observed in an individual with breast cancer (Tung et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8093A>G; Published functional studies demonstrate decreased homology-directed repair (HDR) activity and increased sensitivity to PARP inhibitors (Hart et al., 2019; Ikegami et al., 2020; Richardson et al., 2021; Iversen et al., 2022); This variant is associated with the following publications: (PMID: 32444794, 33609447, 29884841, 12228710, 35665744, 25186627)

This missense variant replaces asparagine with serine at codon 2622 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported conflicting impacts of this variant on BRCA2. Two studies have reported that this variant impacts BRCA2 homology-directed repair activity and in the rescue of PARP inhibitor and carboplatin sensitivities in BRCA2-deficient cells (PMID: 29884841, 32444794). However, a third study reported that this variant does not impact the rescue of cell viability and partially impacts drug sensitivity in Brca2-deficient mouse embryonic stem cell assays (PMID: 33293522). This variant has been observed in an individual affected with breast cancer (PMID: 25186627). This variant also has been reported in 1 individual age 70 years or older without cancer in the FLOSSIES database and identified in 8/282658 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 sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 2622 of the BRCA2 protein (p.Asn2622Ser). This variant is present in population databases (rs142899125, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 91496). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA2 function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA2 function (PMID: 29884841, 32444794, 33293522, 33609447). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.

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