ClinVar Genomic variation as it relates to human health

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

Variant summary: BRCA2 c.9076C>G (p.Gln3026Glu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250082 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9076C>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome or other types cancer (e.g. Kauff_2002, Cheng_2017, Huang_2018, Kim_2019, Fanale_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Casadei_2019, Hart_2019). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS n=3, likely benign/benign n=2). Based on the evidence outlined above, the variant was classified as likely benign.

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 3026 of the BRCA2 protein (p.Gln3026Glu). This variant is present in population databases (rs80359159, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer, melanoma, and/or ovarian cancer (PMID: 12161607, 27376475, 29625052, 31161121, 34178674, 36451132). This variant is also known as c.9304C>G. ClinVar contains an entry for this variant (Variation ID: 52742). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 29884841, 35736817). 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.

This variant is denoted BRCA2 c.9076C>G at the cDNA level, p.Gln3026Glu (Q3026E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAG>GAG). Using alternate nomenclature, this variant has been previously published as BRCA2 9304C>G. This variant has been observed in at least two individuals with suspected Hereditary Breast and Ovarian Cancer (Kauff 2002, Schenkel 2016). BRCA2 Gln3026Glu was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamine and Glutamic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Gln3026Glu occurs at a position that is not conserved and is located in the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Gln3026Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

. According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose this criterium: BP4 (supporting benign): BayesDEL:0.00500399 and spliceAI: BRCA2: 0.07

This missense variant replaces glutamine with glutamic acid at codon 3026 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study reported that this variant has no impact on homology-directed DNA repair (PMID: 29884841). This variant has been detected in at least four individuals affected with breast or ovarian cancer (PMID: 12161607, 31161121, 33471991, 34178674; Leiden Open Variation Database DB-ID BRCA2_000398), an individual affected with skin cancer (PMID: 29625052) and a family suspected of being affected with hereditary breast and ovarian cancer (PMID: 27376475). This variant has been identified in 2/250082 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 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.

PM2(Supporting)+BS3(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)

The BRCA2 c.9076C>G variant is predicted to result in the amino acid substitution p.Gln3026Glu. This variant was reported as a variant of uncertain significance in an individual with skin cancer (Supplementary Table S2B, Huang et al. 2018. PubMed ID: 29625052) and in individuals with breast and ovarian cancer (Table 3, Fanale et al. 2021. PubMed ID: 34178674). Functional studies have shown that this alteration does not affect BRCA2 function (Supplementary Table 2, Hart et al. 2018. PubMed ID: 29884841, Supplementary Table 2, Hu et al. 2022. PubMed ID: 35736817). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/52742/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

The BRCA2 p.Gln3026Glu variant was identified in 2 of 620 proband chromosomes (frequency: 0.003) from individuals or families with hereditary breast and ovarian cancer (Kauff 2002, Schenkel 2016). The variant was also identified in following databases: dbSNP (ID: rs80359159) as "Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry genetics, GeneDx, BIC), Clinvitae, and LOVD 3.0 (as inconclusive). The variant was not identified in COGR, Cosmic, MutDB, UMD-LSDB, BIC Database, ARUP Laboratories, or Zhejiang University Database. The variant was identified in control databases in 2 of 244944 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). It was observed in the European (Non-Finnish) population in 2 of 110742 chromosomes (freq: 0.00002), but not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. One study classified the variant as uncertain significance based on a protein likelihood ratio model (Karchin 2008). The variant was also reported in a study of the incidence of non-founder BRCA1 and BRCA2 mutations in high risk Ashkenazi breast and ovarian cancer families, where it was also classified as a variant of uncertain clinical significance (Kauff 2002). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Gln3026 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. 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 uncertain significance.