Submissions for variant NM_032043.2(BRIP1):c.430G>A (p.Ala144Thr) (rs116952709)

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000120404	SCV000167435	benign	not specified	2013-12-31	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	RCV000131536	SCV000186531	benign	Hereditary cancer-predisposing syndrome	2014-08-08	criteria provided, single submitter	clinical testing	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Invitae	RCV001084094	SCV000218946	benign	Familial cancer of breast; Fanconi anemia, complementation group J	2020-12-07	criteria provided, single submitter	clinical testing
Counsyl	RCV000408974	SCV000489861	benign	Fanconi anemia, complementation group J	2016-08-15	criteria provided, single submitter	clinical testing
Counsyl	RCV000410510	SCV000489862	benign	Neoplasm of ovary	2016-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120404	SCV000600922	benign	not specified	2017-02-07	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000131536	SCV000684280	benign	Hereditary cancer-predisposing syndrome	2015-04-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589730	SCV000699727	benign	not provided	2016-07-01	criteria provided, single submitter	clinical testing	Variant summary: The BRIP1 c.430G>A (p.Ala144Thr) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 164/121364 control chromosomes (2 homozygotes) at a frequency of 0.0013513, which is approximately 22 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589730	SCV000889216	benign	not provided	2017-02-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001286074	SCV001472597	likely benign	none provided	2019-09-04	criteria provided, single submitter	clinical testing
ITMI	RCV000120404	SCV000084556	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000131536	SCV000787970	likely benign	Hereditary cancer-predisposing syndrome	2017-10-26	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000120404	SCV001364459	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	RCV001355323	SCV001550181	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The BRIP1 p.Ala144Thr variant was identified in 7 of 3854 proband chromosomes (frequency: 0.002) from Australian, Korean, Chinese and America individuals or families with suspected Lynch Syndrome, or BRCA1/2 negative familial breast cancer, but was not identified in 186 control chromosomes (Yurgelun 2015, Lewis 2005, Kim 2016 , Cao 2009). In one study, the variant cooccurred with BRIP1 c.3401delC, and both variants were not found to segregate with breast cancer, being inherited from the father of the index case who had no personal or family history of breast cancer, and not from the affected mother with a strong family history (Lewis 2005 ). The variant was identified in ClinVar (classified as benign by GeneDx, Ambry Genetics, Invitae, Counsyl; likely benign by Illumina; and classification not provided by ITMI), Clinvitae ( classified as benign 5X, and likely benign 1X), Cosmic (1X in a bladder carcinoma, confirmed as somatic), and the Zhejiang Colon Cancer Database (3X); and was not identified in MutDB. The variant was also identified in control databases in 390 (2 homozygous) of 277018 chromosomes at a frequency of 0.001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), identified in the following population at a frequency greater than 1%: East Asian in 361 of 18862 chromosomes (freq: 0.019). The p.Ala144Thr residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute	RCV000120404	SCV001905916	benign	not specified		no assertion criteria provided	clinical testing
Human Genetics - Radboudumc,Radboudumc	RCV000120404	SCV001956580	benign	not specified		no assertion criteria provided	clinical testing