Submissions for variant NM_007294.4(BRCA1):c.75C>T (p.Pro25=)

gnomAD frequency: 0.00004  dbSNP: rs80356839

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111695	SCV000578460	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	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/).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080723	SCV000077135	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163150	SCV000213667	likely benign	Hereditary cancer-predisposing syndrome	2014-08-04	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.
Baylor Genetics	RCV000469236	SCV000540981	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000496708	SCV000586861	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000496708	SCV000588023	benign	not specified	2017-04-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755220	SCV000602696	benign	not provided	2017-05-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163150	SCV000683354	likely benign	Hereditary cancer-predisposing syndrome	2015-04-13	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163150	SCV002537896	likely benign	Hereditary cancer-predisposing syndrome	2021-02-03	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149711	SCV003838914	likely benign	Breast and/or ovarian cancer	2021-06-14	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000111695	SCV004016778	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000496708	SCV004026827	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001080723	SCV004228163	likely benign	Hereditary breast ovarian cancer syndrome	2023-10-17	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111695	SCV000144197	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2006-07-19	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353769	SCV000591233	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Pro25Pro variant was identified in the literature (Bowles_2014_Myriad Publ, Ozcelik H_2012_22874498). However, no proband information was available. The variant was identified in dbSNP (ID: rs80356839) “With Likely benign allele”, Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 4 of 120942 chromosomes (frequency: 3.31e-05) from a population of East Asian (4 of 8640 chromosomes) The variant was not found in African, Latino, South Asian, European (Finnish), European (Non-Finnish) and other individuals. The variant was also identified in the ClinVar database (classified as a Benign by BIC and Gene DX and as Likely Benign by Invitae), GeneInsight through the Canadian Open Genetics Repository (http://opengenetics.ca/) (2X, classified as “IARC1 and IARC2” by 2 clinical laboratories), the BIC database (1X with unknown clinical importance).The variant was also previously identified by our laboratory 6X.The Pro25Pro 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 addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. Additionally, at the ACMG Meeting in March 2014, ( Bowles_2014_Myriad Publ) Myriad announced that “BRCA1 c.75C>T (p.Pro25Pro) has been previously observed in a patient with decreased mRNA transcript levels and was postulated to be pathogenic. However, in Myriad’s patient population, this variant co-occurs in trans with known deleterious BRCA1 mutations in five patients and has been found in the homozygous state in 14 patients, strongly indicating a benign classification. History weighting analysis confirms the benign nature of this variant.” In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
King Laboratory, University of Washington	RCV000496708	SCV001251288	benign	not specified	2019-09-01	no assertion criteria provided	research
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000755220	SCV001800683	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000755220	SCV001905757	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000496708	SCV001931191	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000755220	SCV001973316	likely benign	not provided		no assertion criteria provided	clinical testing