Submissions for variant NM_000059.4(BRCA2):c.2233A>G (p.Lys745Glu)

gnomAD frequency: 0.00009  dbSNP: rs374691587

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130703	SCV000185590	likely benign	Hereditary cancer-predisposing syndrome	2018-10-30	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	RCV000985472	SCV000210285	likely benign	not provided	2021-04-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22034289, 20051372, 18284688, 31131967)
Invitae	RCV000197517	SCV000254172	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-13	criteria provided, single submitter	clinical testing
Counsyl	RCV000410547	SCV000488508	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000197517	SCV000838768	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130703	SCV000905803	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-06	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 745 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 18284688, 22034289, 35264596). This variant has been identified in 7/282666 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160045	SCV000916973	uncertain significance	not specified	2022-12-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2233A>G (p.Lys745Glu) 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 1.6e-05 in 251266 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2233A>G has been reported in the literature in individuals affected with breast cancer (e.g. Lee_2008, Fackenthal_2012, Pal_2015, Guindalini_2022). These reports 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. Eight ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments; five submitters classified the variant as uncertain significance, and 3 submitters classified the variant as likely benign. A multifactorial likelihood analysis did not assign an IARC class to the variant (Parsons_2019). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985472	SCV001133703	uncertain significance	not provided	2019-09-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000410547	SCV001139025	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130703	SCV003846593	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000985472	SCV000591795	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA2 c.2233A>G variant has not been reported in the literature nor previously identified by our laboratory. This residue is not highly conserved in mammals and the variant amino acid 745Glu is present in mammals. In addition, computational analyses (SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information alone 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. Classified under. ACMG 3