Submissions for variant NM_000251.2(MSH2):c.505A>G (p.Ile169Val) (rs63750716)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076619	SCV000107654	likely benign	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability 0.001-0.049
GeneDx	RCV000212588	SCV000149444	likely benign	not specified	2017-09-05	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.
Invitae	RCV001086693	SCV000166283	benign	Hereditary nonpolyposis colorectal neoplasms	2020-12-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115535	SCV000183948	likely benign	Hereditary cancer-predisposing syndrome	2018-11-30	criteria provided, single submitter	clinical testing	Co-occurence with mutation in same gene (phase unknown);Does not segregate with disease in family study (genes with incomplete penetrance);In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Color Health, Inc	RCV000115535	SCV000537440	likely benign	Hereditary cancer-predisposing syndrome	2015-02-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212588	SCV000601482	benign	not specified	2017-06-22	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc	RCV000659879	SCV000781770	uncertain significance	Lynch syndrome I	2016-11-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759836	SCV000889441	benign	not provided	2017-06-22	criteria provided, single submitter	clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research	RCV001030707	SCV001193629	likely benign	Hereditary breast and ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Illumina Clinical Services Laboratory,Illumina	RCV000659879	SCV001297031	likely benign	Lynch syndrome I	2018-02-27	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212588	SCV001360857	benign	not specified	2019-11-26	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.505A>G (p.Ile169Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 251484 control chromosomes, predominantly at a frequency of 0.0064 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.505A>G has been reported in the literature in individuals affected with colon cancer and gastric cancer (Tomita_2003, Park_2008, Kim_2017). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Additionally, Park_2008 reports that this variant did not co-segregate with disease in one family. Co-occurrence with a pathogenic variant has been reported (MSH2 c.905T>A, p.Leu302Ter) (Tomita_2003), providing supporting evidence for a benign role. At least one publication reports this variant showed no damaging effect of this variant (Zhu_2013). Six ClinVar submitters including one expert panel (InSiGHT, classified as likely benign in 2013) (evaluation after 2014) cite the variant as uncertain significance (1x), likely benign (3x) and benign (2x). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000759836	SCV001502298	likely benign	not provided	2020-11-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV001355673	SCV001550624	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.Ile169Val variant was identified in 5 of 4626 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer, Lynch syndrome, ovarian cancer or diffuse large B cell lymphoma (Fan 2005, Liu 2014, Miranda 2013, Pal 2012, Ward 2013). The variant was also identified in dbSNP (ID: rs63750716) as "With other allele", ClinVar (classified as benign by Invitae and Quest Diagnostics Nichols Institute San Juan Capistrano; as likely benign by four submitters; and as uncertain significance by Center for Human Genetics). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 124 of 277218 chromosomes (1 homozygous) at a frequency of 0.0005, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 6468 chromosomes (freq: 0.0003) and East Asian in 122 of 18862 chromosomes (freq: 0.007), while the variant was not observed in the African, Latino, European, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Ile169 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.