Submissions for variant NM_000059.4(BRCA2):c.62A>G (p.Lys21Arg)

gnomAD frequency: 0.00004  dbSNP: rs397507367

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000122923	SCV000166181	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129552	SCV000184332	likely benign	Hereditary cancer-predisposing syndrome	2020-06-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
GeneDx	RCV000656792	SCV000210251	uncertain significance	not provided	2018-05-17	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.62A>G at the cDNA level, p.Lys21Arg (K21R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). Using alternate nomenclature, this variant would be defined as BRCA2 290A>G. This variant was observed in at least two individuals with early onset breast cancer (Maxwell 2014, Abdel-Razeq 2018). BRCA2 Lys21Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Lys21Arg is located within the region of interaction with PALB2 (Roy 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Lys21Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl	RCV000031614	SCV000487822	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-11-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129552	SCV000537556	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-29	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 21 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). An RNA study using patient-derived RNA has shown this variant does not impact splicing (PMID: 22505045). A functional study has reported that this variant does not impact BRCA2 function, as assayed by response to PARP inhibitors (PMID: 32444794). This variant has been reported in individuals with a personal and/or family history with breast or ovarian cancer (PMID 25503501, 29409476, 32438681, 33067490). This variant has also been identified in 7/251130 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656792	SCV000600690	uncertain significance	not provided	2021-04-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000122923	SCV000838718	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000031614	SCV001138937	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193807	SCV001362936	likely benign	not specified	2022-07-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.62A>G (p.Lys21Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251130 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.62A>G has been reported in the literature in individuals affected with breast cancer (example, Maxwell 2015, Abdel-Razeq 2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with another pathogenic variant has been reported (BRCA1 c.4986+6T>C; in the UMD database classified as pathogenic), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (example, Ikegami_2020). These results showed no damaging effect of this variant on homology directed repair (HDR). Eight 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 (likely benign, n=2; VUS, n=6). Based on the evidence outlined above, the variant was classified as likely benign.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031614	SCV003932746	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	A variant of uncertain significance was detected in the BRCA2 gene (c.62A>G). This sequence change replaces lysine with arginine at codon 21 of the BRCA2 protein (p.Lys21Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs397507367, ExAC 0.03%). This variant has been reported in individuals affected with breast cancer (PMID: 25503501, 29409476). ClinVar contains an entry for this variant (Variation ID: 38033) with 11 submissions, 10 are described as of uncertain significance and 1 as likely benign. In-silico prediction show benign computational verdict based on 8 benign predictions from PolyPhen, BayesDel_addAF, EIGEN, FATHMM-MKL, MVP, MutationTaster, PrimateAI and SIFT vs 1 pathogenic prediction from M-CAP (and 1 uncertain prediction from DANN) and the position is not strongly conserved. However, these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Therefore, it has been classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP)	RCV000031614	SCV000054221	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-10-31	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357067	SCV001552401	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Lys21Arg variant was not identified in the literature, nor was it identified NHLBI Exome Sequencing Project, Fanconi Anemia Mutation Database (LOVD), COSMIC, ARUP Laboratories BRCA Mutations Database, GeneInsight-COGR, BIC, UMD, or the 1000 Genomes Project. The variant was identified in dbSNP (ID: rs397507367) as “With Uncertain Significance Allele” and in the Exome Aggregation Consortium database (August 8, 2016) in 3 of 116410 chromosomes (frequency: 0.00003) in the African population but was not seen in East Asian, Finnish, European (non-Finnish), Latino and South Asian populations. Furthermore the variant was identified as Uncertain Significance in Clinvitae and Clinvar Databases by Invitae, Ambry Genetics, GeneDx and the Sharing Clinical Reports Project. The p.Lys21residue is not conserved in mammals and five out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and one of five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the creation of a 3’ splice site. 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.