Submissions for variant NM_032043.3(BRIP1):c.587A>G (p.Asn196Ser)

gnomAD frequency: 0.00017  dbSNP: rs550707862

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235147	SCV000150072	likely benign	not specified	2018-01-02	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	RCV000116163	SCV000184386	likely benign	Hereditary cancer-predisposing syndrome	2019-04-04	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.
Invitae	RCV001082539	SCV000253631	benign	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586611	SCV000699731	likely benign	not provided	2017-05-15	criteria provided, single submitter	clinical testing	Variant summary: The BRIP1 c.587A>G (p.Asn196Ser) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a benign outcome for this variant. This variant was found in 55/121326 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.005904 (51/8638). This frequency is about 94 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant has been reported in three East Asian patients with breast cancer in the literature (Cao_2009, Kim_2016), without strong evidence for causality. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely benign. Taken together, this variant is classified as "likely benign".
Color Diagnostics, LLC DBA Color Health	RCV000116163	SCV000910593	benign	Hereditary cancer-predisposing syndrome	2015-04-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586611	SCV001134033	benign	not provided	2023-05-19	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030546	SCV001193542	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV001127949	SCV001287317	likely benign	Fanconi anemia complementation group J	2017-11-07	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.
Genetic Services Laboratory, University of Chicago	RCV000235147	SCV002069343	likely benign	not specified	2019-04-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116163	SCV002533722	benign	Hereditary cancer-predisposing syndrome	2020-12-02	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149814	SCV003837717	likely benign	Breast and/or ovarian cancer	2021-08-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529954	SCV004729821	likely benign	BRIP1-related disorder	2021-04-06	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000235147	SCV005089867	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000235147	SCV001364462	benign	not specified	2019-08-13	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356235	SCV001551349	likely benign	Cervical cancer		no assertion criteria provided	clinical testing	The BRIP1 p.Asn196Ser variant was identified in 5 of 1236 proband chromosomes (frequency: 0.004) from individuals or families with breast cancer (Kim 2016, Liu 2017, Cao 2009). The variant was also identified in dbSNP (ID: rs550707862) as "With Likely benign allele", ClinVar (classified as likely benign by Invitae, Ambry Genetics, GeneDx, and Integrated Genetics). The variant was identified in control databases in 136 of 277096 chromosomes (1 homozygous) at a frequency of 0.0005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6462 chromosomes (freq: 0.0002), Latino in 2 of 34414 chromosomes (freq: 0.00006), European Non-Finnish in 2 of 126626 chromosomes (freq: 0.00002), East Asian in 123 of 18854 chromosomes (freq: 0.007), and South Asian in 8 of 30782 chromosomes (freq: 0.0003), while the variant was not observed in the African, Ashkenazi Jewish or European Finnish populations. The p.Asn196 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356416	SCV001551578	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRIP1 p.Asn196Ser variant was identified in 5 of 1236 proband chromosomes (frequency: 0.004) from individuals or families with breast cancer (Kim 2016, Liu 2017, Cao 2009). The variant was also identified in dbSNP (ID: rs550707862) as "With Likely benign allele", ClinVar (classified as likely benign by Invitae, Ambry Genetics, GeneDx, and Integrated Genetics). The variant was identified in control databases in 136 of 277096 chromosomes (1 homozygous) at a frequency of 0.0005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6462 chromosomes (freq: 0.0002), Latino in 2 of 34414 chromosomes (freq: 0.00006), European Non-Finnish in 2 of 126626 chromosomes (freq: 0.00002), East Asian in 123 of 18854 chromosomes (freq: 0.007), and South Asian in 8 of 30782 chromosomes (freq: 0.0003), while the variant was not observed in the African, Ashkenazi Jewish or European Finnish populations. The p.Asn196 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.