Submissions for variant NM_000059.4(BRCA2):c.280C>T (p.Pro94Ser)

gnomAD frequency: 0.00004  dbSNP: rs80358531

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129340	SCV000184104	likely benign	Hereditary cancer-predisposing syndrome	2019-04-18	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.
Invitae	RCV000168018	SCV000218670	likely benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000589736	SCV000228767	uncertain significance	not provided	2014-09-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589736	SCV000296711	uncertain significance	not provided	2023-05-01	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported individuals with hereditary breast and ovarian cancer (PMID: 29928469 (2018) and 21120943 (2011)). Published studies indicate that this variant does not alter splicing (PMID: 32641407 (2020), 32123317 (2020)) and does not demonstrate allelic imbalance (PMID: 19471317 (2009)). The frequency of this variant in the general population, 0.00014 (5/34570 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV000589736	SCV000321446	likely benign	not provided	2020-12-14	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21120943, 19471317, 25348012, 29659569, 29928469, 32641407, 32123317)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000254706	SCV000694632	likely benign	not specified	2023-08-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.280C>T (p.Pro94Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251082 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4.8e-05 vs 0.00075), allowing no conclusion about variant significance. c.280C>T has been reported in the literature in individuals affected with breast or ovarian cancer and HBOC (example, Caux-Moncoutier_2009, Ortiz_2016, Maksimenko_2018, Guindalini_2022). 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 has been observed (BRCA1 c.5266dup, p.Gln1756fsX74 in UMD database), providing supporting evidence for a benign role. This variant had no effect in a study assessing allelic imbalance as an indirect measure of the impact of out-of-frame defects leading to reductions in the levels of mutant mRNA cleared through NMD (example, Caux-Moncoutier 2009). Consistent with this result, a second study has shown variant has no effect on splicing and classified the variant as benign (Thomassen_ 2022). This supports the notion that this variant has no effect on splicing. The following publications have been ascertained in the context of this evaluation (PMID: 19471317, 21120943, 29928469, 29659569, 35979650, 35264596). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=4) and VUS (n=7). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000168018	SCV000838726	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129340	SCV000910810	likely benign	Hereditary cancer-predisposing syndrome	2017-01-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000031384	SCV001138950	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798039	SCV002042565	uncertain significance	Breast and/or ovarian cancer	2023-06-12	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000254706	SCV002066668	uncertain significance	not specified	2020-11-23	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.280C>T, in exon 3 that results in an amino acid change, p.Pro94Ser. This sequence change does not appear to have been previously described in patients with BRCA2-related disorders and has been described in the gnomAD database with a frequency of 0.014% in the Latino sub-population (dbSNP rs80358531). The p.Pro94Ser change affects a moderately conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro94Ser substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro94Ser change remains unknown at this time.
Genetics Program, Instituto Nacional de Cancer	RCV000168018	SCV002515243	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000129340	SCV002535528	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-28	criteria provided, single submitter	curation
Sharing Clinical Reports Project (SCRP)	RCV000031384	SCV000053989	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-03-22	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031384	SCV000146497	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	RCV000589736	SCV000591672	uncertain significance	not provided		no assertion criteria provided	clinical testing	The p.Pro94Ser variant was identified by Caux-Moncoutier (2009) in a hereditary breast/ovarian cancer (HBOC) patient. The authors of this study used an allelic imbalance assay to assess the putative impact of variants on splicing; no allelic imbalance was found for the variant, suggesting that it does not impact splicing. The variant was also identified in dbSNP (ID: rs80358531) “With non-pathogenic allele”, and three times in UMD as an unclassified variant. The p.Pro94 residue is conserved across mammals and lower organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) suggest that the p.Pro94Ser variant may impact the protein. 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. This variant is classified as a variant of unknown significance.
Department of Medical and Surgical Sciences, University of Bologna	RCV000031384	SCV004228397	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BS1(Supporting)+BP1(Strong)+BP5(Moderate) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
BRCAlab, Lund University	RCV000031384	SCV004243715	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing