Submissions for variant NM_000059.4(BRCA2):c.2339C>G (p.Ser780Ter)

dbSNP: rs587781471

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000241405	SCV000300510	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.
Ambry Genetics	RCV000129415	SCV000184185	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-29	criteria provided, single submitter	clinical testing	The p.S780* pathogenic mutation (also known as c.2339C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 2339. This changes the amino acid from a serine to a stop codon within coding exon 10. This mutation has been identified in multiple individuals and families with hereditary breast and ovarian cancer (HBOC) syndrome (Konstantopoulou I et al. Clin Genet, 2014 Jan;85:36-42; Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11; Chao A et al. Oncotarget, 2016 Dec;7:85529-85541; Kotoula V et al. Am J Cancer Res, 2017 Jan;7:98-114; Apessos A et al. Cancer Genet, 2018 01;220:1-12; Li A et al. Gynecol Oncol, 2018 10;151:145-152; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Dorling et al. N Engl J Med. 2021 02;384:428-439), including a male patient with a personal history of breast and pancreatic cancer and a female patient with renal and uterine cancer (Fostira F et al. Breast Cancer Res Treat, 2018 May;169:105-113; Hartman TR et al. Sci Rep, 2020 08;10:13518). 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.
GeneKor MSA	RCV000484555	SCV000296816	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This variant is a substitution of one nucleotide base resulting in a single amino acid change from Serine to a termination codon at amino acid residue 780 of the BRCA2 gene. It results in a truncated non-functional protein. This variant has been reported in the international literature in patients with breast and/or ovarian cancer (PMID: 24010542, 27157322). The mutation database ClinVar contains entries for this variant (Variation ID: 141070).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000241405	SCV000326692	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000484555	SCV000568457	pathogenic	not provided	2016-09-09	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.2339C>G at the cDNA level and p.Ser780Ter (S780X) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 c.2567C>G. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with breast and/or ovarian cancer (Konstantopoulou 2014, Kwong 2016, Couch 2015) and is considered pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000508058	SCV000605781	pathogenic	Hereditary breast ovarian cancer syndrome	2015-07-29	criteria provided, single submitter	clinical testing	The p.Ser780X variant in BRCA2 has been reported in 2 individuals with breast ca ncer (1 male and 1 female; Konstantopoulou 2014, Couch 2015), and was absent fro m large population studies. This nonsense variant leads to a premature terminati on codon at position 780, which is predicted to lead to a truncated or absent pr otein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In summary, this vari ant meets our criteria to be classified as pathogenic for HBOC in an autosomal d ominant manner based upon predicted impact to the protein and absence in control s.
Invitae	RCV000508058	SCV000635216	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser780*) 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 (rs587781471, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24010542, 27157322). ClinVar contains an entry for this variant (Variation ID: 141070). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000241405	SCV000677758	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-02-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129415	SCV001359103	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-17	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 expected to result in an absent or non-functional protein product. This variant has been observed in a male individual affected with breast cancer and pancreatic cancer (PMID: 24010542, 29335925), five individuals affected with breast or ovarian cancer (PMID: 25452441, 33471991; Leiden Open Variation Database DB-ID BRCA2_003899, 35918668) and at least three hereditary breast and ovarian cancer families (PMID: 27157322, 29446198, 30702160). This variant has been identified in 1/250872 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000508058	SCV001362884	pathogenic	Hereditary breast ovarian cancer syndrome	2019-04-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2339C>G (p.Ser780X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.2426T>G, p.Leu809X; c.2517C>A, p.Tyr839X; c.2830A>T, p.Lys944X). The variant allele was found at a frequency of 4.1e-06 in 245776 control chromosomes (gnomAD). The variant, c.2339C>G, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Konstantopoulou_2014, Couch_2016, Kwong_2016, Chao_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories and one expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000484555	SCV002065845	pathogenic	not provided	2021-06-28	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.2339C>G, which results in the creation of a premature stop codon at amino acid position 780, p.Ser780*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated BRCA2 protein with potentially abnormal function. This pathogenic sequence change has previously been described in individuals with pancreatic cancer, male breast cancer, and individuals with a personal and/or family history of breast and ovarian cancer (PMID: 24010542, 29335925, 27157322, 29446198, 30702160, 25452441). The p.Ser880* pathogenic sequence change is present in the heterozygous state in a single individual in the gnomAD population database (dbSNP rs587781471). This variant has been classified as pathogenic by the expert panel for BRCA1/2 variants in ClinVar.
Sema4, Sema4	RCV000129415	SCV002533311	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-22	criteria provided, single submitter	curation
Baylor Genetics	RCV002250567	SCV004212869	pathogenic	Familial cancer of breast	2021-12-16	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356658	SCV001551888	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Ser780* variant was identified in 7 of 29,390 proband chromosomes (frequency: 0.0002) from individuals or families with hereditary breast and ovarian cancer (Konstantopoulou 2014, Couch 2015, Kwong 2016, Rebbeck 2018, Chao 2016). The variant was identified in dbSNP (rs587781471) as “with pathogenic allele”, ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx, Counsyl and 4 other submitters), LOVD 3.0 (observed 9x) and UMD-LSDB (observed 1x). The variant was identified in control databases in 1 of 250,872 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 1 of 18,388 chromosomes (freq: 0.00005); it was not observed in the African, Latino, Ashkenazi Jewish, Finnish, European, Other and South Asian populations. The c.2339C>G variant leads to a premature stop codon at position 780, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250567	SCV002520941	pathogenic	Familial cancer of breast		no assertion criteria provided	literature only