Submissions for variant NM_000059.4(BRCA2):c.3262C>T (p.Pro1088Ser)

gnomAD frequency: 0.00009  dbSNP: rs80358572

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086347	SCV000072172	benign	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129258	SCV000184018	likely benign	Hereditary cancer-predisposing syndrome	2018-10-31	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.
GeneDx	RCV000585942	SCV000210587	likely benign	not provided	2018-05-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27376475, 28651617, 26517685, 23525077, 20858050, 30151275)
Counsyl	RCV000031410	SCV000488689	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-05-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044159	SCV000694684	benign	not specified	2021-03-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3262C>T (p.Pro1088Ser) 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 4.3e-05 in 233286 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4.3e-05 vs 0.00075), allowing no conclusion about variant significance. c.3262C>T has been reported in the literature as a reportedly somatic occurrence in non-MSI positive samples from patients with esophageal adenocarcinoma (example, Dulac_2013) and in the MSI instable FFPE specimen derived from a patient with hereditary endometrial carcinoma in whom a germline pathogenic variant in the MSH6 gene had been identified (Jori_2015, patient 5, MSI unstable, MSH6 variant c.3729_3732dupATTA). The variant has also been reported as a germline mutation in the literature in patients with breast/ovarian cancer and head and neck squamous cell carcinoma (HNSCC), without strong evidence for causality (example, Coulet_2010, Buzolin_2017, Schenkel_2016, Chandrasekharappa_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple co-occurrences with other pathogenic variant(s) have been reported in the BIC database (2 - BRCA1 exon13ins6kb, 1 - BRCA1 c.3549_3550delinsT (p.K1183fsX), and 1 - BRCA1 c.4357+1G>A), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=8, VUS, n=2). Taken together, based on at-least 5 reports of the occurrence of this variant in patients with an alternative molecular basis of disease attributed to mutations in MSH6 (n=1) or BRCA1 (n=4) genes and the majority concordance among peers supporting a neutral outcome as outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000031410	SCV000743282	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-06-15	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031410	SCV000744436	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000585942	SCV000805688	uncertain significance	not provided	2018-01-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129258	SCV000902754	benign	Hereditary cancer-predisposing syndrome	2016-06-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000585942	SCV001470413	likely benign	not provided	2022-09-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000585942	SCV002497654	uncertain significance	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129258	SCV002533777	likely benign	Hereditary cancer-predisposing syndrome	2022-01-10	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129258	SCV003851815	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).
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV001086347	SCV004228270	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-19	criteria provided, single submitter	curation	BRCA2 "coldspot" variant. According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose these criteria: BP1 (strong benign): missense outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1), BS1 (supporting benign): FAF > 0.00002
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000585942	SCV004563258	likely benign	not provided	2023-03-02	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000031410	SCV005398721	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with BRCA2-associated cancers, complementation group D1 fanconi anemia (MIM#605724) and Wilms tumor (MIM#194070). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a condition (13 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. These alternative changes (p.Pro1088Ala, p.Pro1088Leu) have been reported as VUS (ClinVar). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported multiple times as likely benign, benign and as a VUS (LOVD, ClinVar, PMID: 31131967), and has been observed to be equally distributed among cancer cohorts and controls (PMID: 33471991). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Sharing Clinical Reports Project (SCRP)	RCV000031410	SCV000054015	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2008-10-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031410	SCV000146198	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000585942	SCV000778661	likely benign	not provided	2017-07-27	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000585942	SCV001743080	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000585942	SCV001905951	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000585942	SCV001960092	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000585942	SCV002036082	likely benign	not provided		no assertion criteria provided	clinical testing