Submissions for variant NM_000059.4(BRCA2):c.5552T>G (p.Ile1851Ser)

gnomAD frequency: 0.00005  dbSNP: rs80358776

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031553	SCV001161519	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00059
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081549	SCV000072692	benign	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131533	SCV000186527	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000034447	SCV000210614	likely benign	not provided	2021-05-02	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22703879, 16683254, 22366370, 27376475, 24817641, 20167696, 18403564, 31131967)
Fulgent Genetics, Fulgent Genetics	RCV000031553	SCV000575750	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-01-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131533	SCV000683711	likely benign	Hereditary cancer-predisposing syndrome	2015-04-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044679	SCV000918861	benign	not specified	2022-05-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5552T>G (p.Ile1851Ser) 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 5.2e-05 in 269076 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (5.2e-05 vs 0.00075), allowing no conclusion about variant significance. c.5552T>G has been reported in the literature in individuals affected with breast cancer and/or ovarian cancer (Levanat_2012, Schenkel_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. The variant has also been reported in two cancer-free individuals older than age 70 (FLOSSIES database), suggesting a non-pathogenic role. At-least one co-occurrence with another pathogenic variant(s) have been reported in the BIC database (BRCA2 c.5351dupA, p.Asn1784fsX3), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as benign (including the expert panel)/likely benign (n=7) (VUS, n=2). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000034447	SCV001148986	likely benign	not provided	2022-03-01	criteria provided, single submitter	clinical testing	BRCA2: BP4
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000044679	SCV001157757	uncertain significance	not specified	2018-07-17	criteria provided, single submitter	clinical testing	The BRCA2 c.5552T>G; p.Ile1851Ser variant (rs80358776), to our knowledge, has not been described in the medical literature but contains an entry in ClinVar (Variation ID: 37972). It is observed in the European (Non-Finnish) population at an overall frequency of 0.01% (11/110504 alleles) in the Genome Aggregation Database. The isoleucine at codon 1851 is weakly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. However, due to lack of clinical and functional data regarding this variant, its clinical significance cannot be determined with certainty.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034447	SCV001470429	likely benign	not provided	2020-02-26	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798047	SCV002043196	likely benign	Breast and/or ovarian cancer	2022-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131533	SCV002536146	likely benign	Hereditary cancer-predisposing syndrome	2021-03-21	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000044679	SCV004027440	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034447	SCV000043214	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000031553	SCV000054158	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2008-12-10	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031553	SCV000146632	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031553	SCV004243672	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541041	SCV004766425	likely benign	BRCA2-related disorder	2019-12-05	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).