Submissions for variant NM_000059.4(BRCA2):c.6935A>T (p.Asp2312Val)

gnomAD frequency: 0.00003  dbSNP: rs80358916

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113673	SCV001161534	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000027
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045088	SCV000073101	benign	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163021	SCV000213509	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000045088	SCV000257615	likely benign	Hereditary breast ovarian cancer syndrome	2015-07-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000243078	SCV000301769	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000113673	SCV000383752	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000328837	SCV000383753	likely benign	Fanconi anemia complementation group D1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Counsyl	RCV000113673	SCV000488811	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-07-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000243078	SCV000516689	benign	not specified	2017-12-07	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000163021	SCV000679723	likely benign	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163021	SCV000683829	likely benign	Hereditary cancer-predisposing syndrome	2016-07-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586654	SCV000695008	likely benign	not provided	2016-06-27	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.6935A>T (p.Asp2312Val) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict damaging outcome for this variant. This variant is only three nucleotides away from the nearest exon-intron boundary and is thus predicted to affect normal splicing. 3/5 splice prediction tools predict a significant impact on normal splicing. But in vitro studies show that this variant does not significantly affect normal splicing (Houdayer_2011, Brandao_2011). This variant was found in 32/113924 control chromosomes (including one homozygote), predominantly observed in the South Asian, subpopulation at a frequency of 0.0016915 (27/15962). This frequency is about 2 times higher than the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian. This variant has been reported in several instances in HBOC patients and/or individuals undergoing BRCA1/2 testing including co-occurrence with another deleterious variant (p.Lys1026Ter) in the same gene, strongly supporting for the benign outcome. Multifactorial probability-based models are also consistent with the benign outcome. Multiple clinical labs have classified this variant as benign/likely benign. Taken together, this variant is currently classified as Likely Benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586654	SCV000889116	benign	not provided	2023-09-08	criteria provided, single submitter	clinical testing
Mendelics	RCV000113673	SCV001139160	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163021	SCV002536283	benign	Hereditary cancer-predisposing syndrome	2021-12-16	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002496694	SCV002808366	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2022-05-04	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000243078	SCV004027467	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000113673	SCV004844331	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113673	SCV000146971	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000586654	SCV000592083	likely benign	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Asp2312Val variant was identified in 3 of 4718 proband chromosomes (frequency: 0.0006) from Brazilian, German and Other individuals or families at high risk of breast and ovarian cancers, and was present in 1 of 230 control chromosomes (frequency: 0.004) from healthy elderly Croatian women (Fernandes 2016, Trujillano_2015, Brandao 2011). The variant was identified by Brandao (2011) in an individual from a high-risk breast and/or ovarian cancer family and RT-PCR transcript analysis of lymphocytes from this individual showed an increase in exon12 skipping as compared to normal controls; however, the BRCA2 exon 12 deletion isoform is naturally occurring and the c.6935T allele expressed full-length transcript at similar expression levels compared with the wild-type (WT) allele and control alleles suggesting the variant is likely to be neutral. Li (2009) studied a different variant in this region which was also shown to increase exon 12 skipping, and functional results from this study did not detect any difference between this variant and wild type, suggesting that exon 12 is functionally redundant and missense changes in this region are likely to be neutral. In addition, Li (2009) notes that the peptide encoded by exon 12 does not contain any known important functional motifs; however, this region may have a role in processes that were not assessed. An in silico likelihood-ratio study by Easton (2007) suggests that this variant is neutral. In addition, a splice study using 6 in silico models, with predictions compared to transcript analysis showed the variant does not effect change on splicing (Houdayer 2012). The variant was also identified in dbSNP (ID: rs80358916), ClinVar (with conflicting interpretations of pathogenicity; classified as benign by Ambry Genetics, Counsyl, Invitae; likely benign by Prevention Genetics, Div of Genomic Diagnostics - Children's Hospital of Philadelphia, Illumina Clinical Services, GeneDx; and uncertain significance by BIC), Clinvitae (5X), LOVD 3.0 (4x), UMD-LSDB (10X, 1-neutral), and the BIC Database (5x, clinical importance unknown, classification pending). The variant was not identified in the COGR, Cosmic, ARUP Laboratories, and Zhejiang Colon Cancer Databases. The variant was also identified in control databases in 64 (1 homozygous) of 276074 chromosomes at a frequency of 0.0002 in the following populations: other in 1 of 6424 chromosomes (freq. 0.00016), European in 2 of 126058 chromosomes (freq. 0.000016), Ashkenazi Jewish in 1 of 10110 chromosomes (freq. 0.0001), South Asian in 60 of 30712 chromosomes (freq. 0.0002), increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017). The variant was also identified by our laboratory in 3 individuals with breast and ovarian cancer. The p.Asp2312 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The p.Asp2312Val variant occurs in the 3rd last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign
BRCAlab, Lund University	RCV000113673	SCV004243742	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing