Submissions for variant NM_000059.4(BRCA2):c.9728C>T (p.Pro3243Leu)

gnomAD frequency: 0.00002  dbSNP: rs80359241

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167844	SCV000073905	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000587179	SCV000210692	likely benign	not provided	2018-04-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21218378)
Ambry Genetics	RCV000166251	SCV000217031	likely benign	Hereditary cancer-predisposing syndrome	2018-06-20	criteria provided, single submitter	clinical testing	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587179	SCV000296526	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0002 (4/19940 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, this variant has been reported in individuals affected with breast cancer (PMIDs: 36329109 (2022), 33471991 (2021) and 21218378 (2010)), as well as in individuals at high-risk for hereditary breast and/or ovarian cancer (PMID: 31742824 (2020)). It has also been observed in healthy control individuals (PMIDs: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/) and 32467295 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Counsyl	RCV000031845	SCV000487774	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-11-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000045892	SCV000602772	uncertain significance	not specified	2016-08-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045892	SCV000695266	likely benign	not specified	2024-01-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9728C>T (p.Pro3243Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251118 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9728C>T has been reported in the literature as a VUS in settings of individuals affected with and/or undergoing multigene panel testing for Hereditary Breast And Ovarian Cancer (e.g., Carney_2010, Shao_2020) as well as in at least one individual diagnosed with triple-negative breast cancer (e.g., Matta_2022), however without strong evidence for causality in these instances (e.g., lack of co-segregation data). These reports therefore do 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. The following publications have been ascertained in the context of this evaluation (PMID: 21218378, 32467295, 36329109, 28508593, 31742824). ClinVar contains an entry for this variant (Variation ID: 38262). Based on an emerging peer consensus and the lack of any evidence supporting an actionable outcome as outlined above, the variant was re-classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000166251	SCV000902988	likely benign	Hereditary cancer-predisposing syndrome	2017-04-03	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000167844	SCV002515167	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000166251	SCV002532056	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-26	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV004532473	SCV004115849	uncertain significance	BRCA2-related disorder	2022-12-29	criteria provided, single submitter	clinical testing	The BRCA2 c.9728C>T variant is predicted to result in the amino acid substitution p.Pro3243Leu. This variant was reported in a breast cancer patient with Korean-Hawaiian ancestry (see patient #45 in Table 1, Carney et al. 2010. PubMed ID: 21218378), however the patient had a family member with breast cancer who was positive for a different uncertain BRCA2 variant and it is unclear if the p.Pro3243Leu variant was a cause of disease. This variant was also reported in two Chinese breast cancer cohort studies (Supplementary Table S2, Shao et al. 2019. PubMed ID: 31742824; Supplementary Table 1, Dong et al. 2021. PubMed ID: 32467295). Computational functional effect prediction programs classified this variant as probably benign (Pejaver et al. 2017. PubMed ID: 28508593). This variant is reported in 0.020% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32972378-C-T) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/38262/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV000031845	SCV004846224	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-03	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031845	SCV000054453	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2010-09-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031845	SCV000147704	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353590	SCV000592305	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Pro3243Leu variant was not identified in the literature, nor was it identified in NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, COSMIC, GeneInsight VariantWire, BIC or UMD. The variant was identified in the dbSNP database (ID#:rs80359241), but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined; the Exome Aggregation Consortium (ExAC) (released Oct 20th, 2014) in 2 of 121336 chromosomes (frequency: 0.0000) from a population of East Asian (2/8642 individuals), and not in European (Non-Finnish or Finnish), Other, African, Latino, South Asian individuals; and, it was identified in ClinVar (classified as a likely benign variant by the Sharing Clinical Reports Project, derived from Myriad reports; classified as uncertain significance by BIC; and classification not provided by Invitae). The Breast Cancer IARC database notes a weak/null probability the variant creates a de novo splice donor at nt 9728 and a low probability of creating a de novo splice acceptor at nt 9736. The p.Pro3243 residue is not conserved in mammals and lower organisms 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. The c.9728C>T 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. 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 unknown significance.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735633	SCV000863771	uncertain significance	Breast and/or ovarian cancer	2014-11-21	no assertion criteria provided	clinical testing