Submissions for variant NM_000059.4(BRCA2):c.441A>G (p.Gln147=)

gnomAD frequency: 0.00001  dbSNP: rs80358676

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083105	SCV000578756	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044411	SCV000072424	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing
GeneDx	RCV001719795	SCV000210239	likely benign	not provided	2019-05-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20492709, 21523855, 10923033, 30883759, 32123317)
Ambry Genetics	RCV000163773	SCV000214354	likely benign	Hereditary cancer-predisposing syndrome	2014-10-06	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	RCV000163773	SCV000683620	likely benign	Hereditary cancer-predisposing syndrome	2015-10-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160020	SCV001363894	likely benign	not specified	2024-07-08	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.441A>G alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic exonic 3' splice acceptor site. However, the functional studies have reported conflicting results. One reported experimental evidence through a mini-gene assay that this variant affects mRNA splicing leading to the formation of aberrant transcripts (Fraile-Bethencourt_2019), while the other reported no effect on splicing following cDNA analysis of patient blood samples (Wai_2020). The variant allele was found at a frequency of 3.6e-05 in 250978 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.441A>G has been reported in the literature as a VUS in settings of individuals affected with/undergoing genetic testing for Hereditary Breast And Ovarian Cancer Syndrome (example, Capone_2018, Wai_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) have been observed in the BIC database (BRCA1 c.2389_2390delGA, p.Glu797fs), providing supporting evidence for a benign role. 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: 29061375, 30883759, 21523855, 32123317). ClinVar contains an entry for this variant (Variation ID: 51645). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001719795	SCV004219628	uncertain significance	not provided	2020-03-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492351	SCV004240312	likely benign	Breast and/or ovarian cancer	2022-10-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000160020	SCV004242649	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000083105	SCV004846775	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-18	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083105	SCV000115179	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083105	SCV000146868	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	RCV001354889	SCV001549608	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The BRCA2 p.Gln147= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs80358676) as "With Likely benign, Uncertain significance allele”, ClinVar (classified as benign by Sharing Clinical Reports Project (SCRP); likely benign by Invitae, GeneDx, Ambry Genetics and two other submitters; as uncertain significance by BIC), LOVD 3.0 (1x as VUS), and in UMD-LSDB (3x as unclassified variant). The variant was identified in control databases in 8 of 245952 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 8 of 111510 chromosomes (freq: 0.00007), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Gln147= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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.