Submissions for variant NM_000059.4(BRCA2):c.10222A>T (p.Lys3408Ter)

gnomAD frequency: 0.00004  dbSNP: rs80358402

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000043728	SCV000071741	benign	Hereditary breast ovarian cancer syndrome	2025-01-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000759573	SCV000108594	likely benign	not provided	2022-07-25	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Ambry Genetics	RCV000131732	SCV000186772	likely benign	Hereditary cancer-predisposing syndrome	2019-03-12	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.
Color Diagnostics, LLC DBA Color Health	RCV000131732	SCV000683399	likely benign	Hereditary cancer-predisposing syndrome	2017-02-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000112851	SCV000785078	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759573	SCV000888974	likely benign	not provided	2023-01-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212295	SCV000918936	likely benign	not specified	2025-01-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.10222A>T (p.Lys3408X) results in a premature termination codon, predicted to cause a truncation of the encoded protein but not expected to undergo nonsense mediated decay. The variant allele was found at a frequency of 1.7e-05 in 1613940 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer Syndrome (1.7e-05 vs 0.00075), allowing no conclusion about variant significance. c.10222A>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome without strong evidence for or against pathogenicity (example: Pirim_2020, Darst_2021, Bisgin_2022). These report(s) 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: 32599251, 32853339, 35753294). ClinVar contains an entry for this variant (Variation ID: 51056). Based on the evidence outlined above, the variant was classified as likely benign.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112851	SCV000145768	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000112851	SCV000592318	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The p.Lys3408X variant was not identified in the literature but was identified in the BIC database (1X with no clinical importance), dbSNP (ID: rs80358402), and in the ClinVar database (classified as likely benign by GeneDx and Ambry Genetics; classified as benign by BIC; classification not provided by Invitae). The variant was listed in the Exome Aggregation Consortium (ExAC) database in 1 of 65858 chromosomes (frequency: 0.00002) from a population of European (Non-Finnish) individuals; however, this single observation and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant results in termination of translation at amino acid position 3408 and the loss of the terminal 9 amino acids of the expressed BRCA2 protein. Borg (2010) identified three variants in the BRCA2 gene near the 3’-end which were predicted to result in protein truncation (c.9976A>T (BIC: K3326X), c.10095delCins11 (BIC: 10323delCins11), c.10150C>T (BIC: R3384X), but were “ruled as exceptions that could not be classified because of their location near the 3’-end and possibly dispensable part of the gene”. The p.Lys3408X variant is located even farther downstream than these variants (i.e. closer to the 3’- end of the gene). Stop codon or nonsense mutations in the last exon of a gene may not be subjected to nonsense mediated RNA decay, although further study would be required to validate this hypothesis and it is currently not possible to determine whether or not this might influence the severity of the disorder. Segregation and/or functional studies are recommended to further elucidate the pathogenicity of this variant. 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.