Submissions for variant NM_000059.4(BRCA2):c.4889C>G (p.Ser1630Ter)

gnomAD frequency: 0.00001  dbSNP: rs80358711

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077340	SCV000300794	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000044512	SCV000072525	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1630*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80358711, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 12920083, 17624602, 22762150). This variant is also known as 5117C>G. ClinVar contains an entry for this variant (Variation ID: 51732). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131080	SCV000186010	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-05	criteria provided, single submitter	clinical testing	The p.S1630* pathogenic mutation (also known as c.4889C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 4889. This changes the amino acid from a serine to a stop codon within coding exon 10. This mutation has been previously reported in French, Italian, Colombian, and Hispanic American hereditary breast and ovarian cancer families (Ottini L et al. Breast Cancer Res. 2000 Mar;2:307-10; Ozcelik H et al. J. Med. Genet. 2003 Aug;40:e91; Claus EB et al. JAMA. 2005 Feb;293:964-9; Monnerat C et al. Fam. Cancer. 2007 Jul;6:453-61; Rodriguez AO et al. Gynecol. Oncol. 2012 Feb;124:236-43). Of note, this mutation is also designated as S1630X or 5117C>G in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Eurofins Ntd Llc (ga)	RCV000255089	SCV000225188	pathogenic	not provided	2016-11-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255089	SCV000296626	pathogenic	not provided	2020-10-22	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast cancer in the published literature (PMID: 29446198 (2018), 24549055 (2014), 25342642 (2014), 22762150 (2012), 17624602 (2007), 15728167 (2005), 12920083 (2003)). The frequency of this variant in the general population is consistent with pathogenicity. Therefore, the variant is classified as pathogenic.
GeneDx	RCV000255089	SCV000321464	pathogenic	not provided	2020-10-14	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in multiple individuals with breast and/or ovarian cancer (Ozcelik 2003, Claus 2005, Malone 2006, Rodriguez 2012, Castera 2014, Zugazagoitia 2014, Pellegrino 2016); Not observed at a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as c.5117C>G; This variant is associated with the following publications: (PMID: 25525159, 15728167, 29767749, 30263092, 17624602, 22762150, 24549055, 24880342, 15131399, 26659639, 26586665, 25342642, 20730485, 27163896, 11056688, 22044689, 16912212, 28831036, 29021639, 30487452, 28127413, 30430080, 29446198, 30720243, 30322717, 12920083, 32341426, 30787465, 31447099)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077340	SCV000327100	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131080	SCV000537669	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-07	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is also known as 5117C>G in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in at least 10 Individuals and families affected with breast and ovarian cancer (PMID: 11056688, 12920083, 15131399, 16912212, 17624602, 22044689, 23884708, 24549055, 25342642, 28831036, 33471991; Leiden Open Variation Database DB-ID BRCA2_002196) and an individual affected with prostate cancer (PMID: 23569316). This variant has been identified in 2/248994 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044512	SCV000605799	pathogenic	Hereditary breast ovarian cancer syndrome	2016-10-04	criteria provided, single submitter	clinical testing	The p.Ser1630X variant in BRCA2 has been reported in at least 15 individuals wit h BRCA2-associated cancers (Castera 2014, Castro 2013, Lecarpentier 2012, Ozceli k 2003, Zugazagoitia 2014, Breast Cancer Information Core database, www.research .nhgri.nih.gov/bic/). This variant has been identified in 2/65832 European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs80358711). This frequency is low enough to be consistent with the freq uency of hereditary breast and ovarian cancer (HBOC) in the general population. This nonsense variant leads to a premature termination codon at position 1630, w hich is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in HBOC. In addi tion, this variant was classified as Pathogenic on September 8, 2016 by the Clin Gen-approved ENIGMA expert panel (ClinVar SCV000300794.2). In summary, this vari ant meets criteria to be classified as pathogenic for HBOC in an autosomal domin ant manner based upon the predicted impact to the protein.
Counsyl	RCV000077340	SCV000677680	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-01-04	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000255089	SCV000693568	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This variant is a single amino acid change from Serine to a termination codon at amino acid residue 1630 of the BRCA2 gene. This is expected to result in an absent or disrupted protein product. Truncating variants in the BRCA2 gene are known to be pathogenic. This variant is also known as c.5117C>G in the literature. This particular variant has been reported in the international literature in families and individuals affected with breast cancer (PMID: 12920083, 22762150, 17624602). The mutation database ClinVar contains an entry for this variant (Variation ID: 51732).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044512	SCV001361806	pathogenic	Hereditary breast ovarian cancer syndrome	2019-03-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4889C>G (p.Ser1630X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.1e-06 in 245816 control chromosomes (gnomAD). c.4889C>G has been reported in the literature in multiple individuals and families affected with breast and/or ovarian cancer (Rebbeck_2018, Castera_2014, McVeigh_2014, Rodriguez_2012, Malone_2006, Ozcelik_2003, Ottini_2000). These data indicate that the variant is very likely to be associated with disease. Eleven ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000255089	SCV001961400	pathogenic	not provided	2021-08-01	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077340	SCV000109137	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-02-08	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077340	SCV000146499	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044512	SCV000587730	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research