Submissions for variant NM_000059.4(BRCA2):c.9270C>T (p.Phe3090=)

gnomAD frequency: 0.00002  dbSNP: rs587780873

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000410788	SCV000579141	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
GeneDx	RCV000124014	SCV000167420	benign	not specified	2014-03-19	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000163089	SCV000213592	likely benign	Hereditary cancer-predisposing syndrome	2015-04-21	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.
Eurofins Ntd Llc (ga)	RCV000724624	SCV000228186	uncertain significance	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081920	SCV000283362	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000410788	SCV000489390	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000474408	SCV000541062	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163089	SCV000684045	likely benign	Hereditary cancer-predisposing syndrome	2015-08-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000124014	SCV000695229	likely benign	not specified	2017-11-06	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.9270C>T (p.Phe3090Phe) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation Taster predicts a damaging outcome for this variant implicating “splice site changes”, however 5/5 splice prediction tools in Alamut predict no significant impact on normal splicing. ESE finder predicts that this variant may affect the binding site of the splicing factor SRp55, however a functional study found that the variant doesn’t affect splicing in lymphocytes (Quiles 2016). This variant was found in 8/276150 control chromosomes at a frequency of 0.000029, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant, to our knowledge, has not been published in the literature as a germline variant in HBOC affected individuals, however the variant has been reported as a somatic mutation in a serous endometrial carcinoma and malignant melanomas (COSMIC). In addition, multiple clinical diagnostic laboratories classified this variant as benign or likely benign. Taken together, this variant is classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000724624	SCV004220646	likely benign	not provided	2023-08-08	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000724624	SCV001550211	likely benign	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Phe3090= variant was not identified in the literature nor was it identified in the following databases: COGR, MutDB, LOVD 3.0, UMD-LSDB, BIC Database, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs587780873) as “With Uncertain significance, other allele”, ClinVar and Clinvitae (classified as benign by GeneDx and Baylor Miraca Genetics, classified as likely benign by Color Genomics, Ambry Genetics, Invitae, Counsyl and ENIGMA, classified as uncertain significance by Laboratory Corporation of America and EGL Genetic Diagnostics), and in the COSMIC database (reported in one case of serous carcinoma of the endometrium and confirmed somatic in 5 cases of malignant melanoma). The variant was identified in control databases in 8 of 276150 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24000 chromosomes (freq: 0.00004), European Non-Finnish in 6 of 126022 chromosomes (freq: 0.00005), East Asian in 1 of 18836 chromosomes (freq: 0.00005), but not in the Other, Latino, Ashkenazi Jewish, European Finnish, and South Asian populations. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing upstream of the variant; this is not very predictive of pathogenicity. The p.Phe3090= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In summary, based on the above information this variant is classified as likely benign.