Submissions for variant NM_000059.3(BRCA2):c.4241C>T (p.Thr1414Met) (rs70953664)

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113286	SCV000245031	benign	Breast-ovarian cancer, familial 2	2015-01-12	reviewed by expert panel	curation	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.0122 (African), derived from 1000 genomes (2012-04-30).
Invitae	RCV000167832	SCV000072388	benign	Hereditary breast and ovarian cancer syndrome	2020-12-07	criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000120327	SCV000202286	benign	not specified	2015-05-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162766	SCV000213243	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: 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.
Counsyl	RCV000113286	SCV000220272	benign	Breast-ovarian cancer, familial 2	2014-04-25	criteria provided, single submitter	literature only
Vantari Genetics	RCV000162766	SCV000267016	likely benign	Hereditary cancer-predisposing syndrome	2015-12-21	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories,University of Michigan	RCV000113286	SCV000267764	benign	Breast-ovarian cancer, familial 2	2016-04-21	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000113286	SCV000383695	likely benign	Breast-ovarian cancer, familial 2	2018-10-29	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina	RCV000346290	SCV000383696	likely benign	Fanconi anemia, complementation group D1	2018-10-29	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000167832	SCV000494351	benign	Hereditary breast and ovarian cancer syndrome	2014-03-06	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000113286	SCV000575755	likely benign	Breast-ovarian cancer, familial 2	2016-01-29	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120327	SCV000593716	likely benign	not specified	2017-02-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001283466	SCV000602745	benign	none provided	2019-11-08	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000162766	SCV000683605	likely benign	Hereditary cancer-predisposing syndrome	2015-03-06	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000113286	SCV000744453	likely benign	Breast-ovarian cancer, familial 2	2015-09-21	criteria provided, single submitter	clinical testing
ITMI	RCV000120327	SCV000084479	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113286	SCV000146394	benign	Breast-ovarian cancer, familial 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV001353946	SCV000591896	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Thr1414Met variant was identified in 4 of 7918 chromosomes (frequency: 0.001) from individuals with breast or ovarian cancer, and in 1 of 148 control chromosomes (frequency: 0.007) from these studies (Borg 2010, Fackenthal 2005, Lee 2007, Palomba 2009). It is listed in dbSNP (ID#: rs70953664) with a “global minor allele frequency" of 0.003 (1000 Genomes), and in the Exome Variant Server ESP project with a frequency of 0.007 in African American alleles, increasing the likelihood that this is a low frequency benign variant in certain populations of origin. This variant was identified in LOVD, in BIC 38X with no clinical importance, and in UMD 3X as a “neutral” variant where it was reported to co-occur with a known BRCA2 pathogenic mutation (BRCA2 c.6159delT (p.Ala2054LeufsX16)), further increasing the likelihood that this variant is benign. The p.Thr1414 residue is not conserved through evolution, with the variant amino acid Methionine (Met) present in mouse, rat and cat; and computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000656603	SCV000778673	likely benign	not provided	2017-07-24	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute	RCV000120327	SCV001905929	benign	not specified		no assertion criteria provided	clinical testing
Human Genetics - Radboudumc,Radboudumc	RCV000120327	SCV001957277	benign	not specified		no assertion criteria provided	clinical testing