Submissions for variant NM_007294.4(BRCA1):c.3415AGT[1] (p.Ser1140del)

dbSNP: rs80358337

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001084973	SCV000076201	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131331	SCV000186305	likely benign	Hereditary cancer-predisposing syndrome	2018-07-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV000048188	SCV000209953	likely benign	not specified	2018-01-25	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.
Counsyl	RCV000112093	SCV000488758	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131331	SCV000683102	likely benign	Hereditary cancer-predisposing syndrome	2015-07-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048188	SCV000699031	likely benign	not specified	2023-01-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3418_3420delAGT (p.Ser1140del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2e-05 in 251122 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3418_3420delAGT has been reported in the literature as a VUS in individual(s) affected with- or at risk for Hereditary Breast and Ovarian Cancer (Judkins 2005). Furthermore, it has been reported in a family affected with cutaneous malignant melanoma, where it was determined not to co-segregate with the disease (Goldstein 2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) has been reported in the BIC database (BRCA1 c.5263_5264insC, p.Ser1755?fs), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (Bouwman_2020). These results showed no damaging effect of this variant on Homologous recombination DNA repair (HRR) by their ability to complement Brca1-deficient mouse embryonic stem cells in HRR, using cisplatin and olaparib sensitivity assays and a direct repeat GFP (DR-GFP) HRR assay. HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG BS3) as sufficient weightage for categorization as likely benign (Tavtigian_2018). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=4; likely benign, n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000112093	SCV001440669	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2019-01-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000203658	SCV001469380	uncertain significance	not provided	2020-08-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131331	SCV002538205	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-15	criteria provided, single submitter	curation
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112093	SCV000144759	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355449	SCV001550335	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Ser1140del variant was not identified in the GeneInsight-COGR, Cosmic, MutDB, ARUP Laboratories, Zhejiang Colon Cancer Database, databases. The variant was identified in dbSNP (ID: rs80358337) as “With Uncertain significance allele”; in ClinVar as likely benign by Invitae, Ambry Genetics and GeneDx, and with uncertain Significance by Counsyl and Breast Cancer Information Core. The variant was further identified in LOVD 3.0 4X with unknown significance, in UMD-LSDB database 3X as UV with no co-occurrence, in BIC Database 3X with unknown clinical significance with pending clinical classification. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Ser1140del variant has been found to reside in trans with known deleterious mutations. Functional studies of transgenic mice support the hypothesis that biallelic BRCA1 result in embryonic lethality. Therefore, it may be concluded that variants of unknown significance residing in trans with known deleterious mutations impart reduced risk for cancer (Judkins 2005). This variant is an in-frame deletion resulting in the removal of a serine residue at codon 1140; the impact of this alteration on BRCA1 protein function is not known. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Breast cancer type 1 susceptibility protein BRCA1 functional domain increasing the likelihood that it may have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Department of Medical and Surgical Sciences, University of Bologna	RCV000112093	SCV004228348	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-01	no assertion criteria provided	clinical testing	BS3(Strong)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)