Submissions for variant NM_000059.4(BRCA2):c.7307A>T (p.Asn2436Ile)

gnomAD frequency: 0.00001  dbSNP: rs80358955

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113744	SCV000244470	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-10	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 = 0.000234
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045184	SCV000073197	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163011	SCV000213499	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.
GeneDx	RCV001284101	SCV000528561	likely benign	not provided	2019-03-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17924331, 11149425, 29338689, 29770616, 21990134, 24323938, 28866612, 28111427, 29192238, 28591652, 29731985, 30415210, 32444794, 32426482)
Color Diagnostics, LLC DBA Color Health	RCV000163011	SCV000903131	benign	Hereditary cancer-predisposing syndrome	2015-12-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000429461	SCV000918953	benign	not specified	2019-10-10	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7307A>T (p.Asn2436Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 298704 control chromosomes in the gnomAD database. However, the variant was reported in some East Asian subpopulations with an even higher allele frequency, e.g. in the Japanese, with an allele frequency of 0.0039 (in the jMorp database). This frequency is about 5 fold higher than the maximum expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (0.00075), suggesting the variant could be a benign polymorphism found in population(s) from East Asia. The variant, c.7307A>T, has been reported in the literature in individuals of East Asian origin, who were affected with breast and/or ovarian cancer and fallopian tube carcinoma (Choi_2018, Kim_2017, Ikeda_2001). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Two recent case-control association studies, involving breast cancer patients and controls of Korean (Park_2017) and Japanese ancestry (Momozawa_2018), found that the variant is not associated with a significant increase risk for breast/ovarian cancer, and therefore the authors of these studies classified the variant as likely benign/benign, respectively. In addition, IARC class based on posterior probability from multifactorial likelihood analysis suggests the variant to be benign (Lindor_2012, Easton_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other submitters, including one expert panel (ENIGMA) have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as likely benign (2x) / benign (2x). Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000113744	SCV001139177	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284101	SCV001469707	likely benign	not provided	2023-01-27	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113744	SCV000147066	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	RCV001355006	SCV001549759	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Asn2436Ile variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs80358955) as With Uncertain significance allele, ClinVar (classified as benign by ENIGMA, Ambry Genetics; classified as likely benign by GeneDx; classified as uncertain significance by Invitae, BIC), LOVD 3.0 (predicted neutral), UMD-LSDB (1X classified as uncertain significance), BIC Database (2X with unknown clinical importance), ARUP Laboratories (with not pathogenic or of no clinical significance), databases. The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 3 of 246016 chromosomes at a frequency of 0.000012, however with this low number the prevalence of this variant in the general population could not be determined. (Genome Aggregation Consortium Feb 27, 2017). The p.Asn2436 residue is not conserved in mammals and four 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant is located with the Breast cancer type 2 susceptibility protein functional domain increasing the likelihood that it may have clinical significance. In addition, functional study by Easton (2007) identify the variant has odds in favor of neutrality 132 and cosegregation with disease in pedigree-.41. 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.