ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1787A>G (p.Asn596Ser) (rs41295288)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200985 SCV000149420 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.
Invitae RCV001081309 SCV000153982 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115511 SCV000187001 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing This alteration is classified as 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034554 SCV000780663 uncertain significance not provided 2018-01-01 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659882 SCV000781774 uncertain significance Lynch syndrome I 2016-11-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000034554 SCV000806012 likely benign not provided 2017-10-27 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115511 SCV000822048 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000076286 SCV000837838 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765668 SCV000897010 uncertain significance Lynch syndrome I; Turcot syndrome; Muir-Torré syndrome 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115511 SCV000902601 benign Hereditary cancer-predisposing syndrome 2015-11-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000200985 SCV000917713 likely benign not specified 2020-10-15 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1787A>G (p.Asn596Ser) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 254316 control chromosomes, predominantly at a frequency of 0.00055 within the Latino subpopulation in the gnomAD database. This frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (0.00055 vs 0.00057), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1787A>G has been reported in the literature in individuals affected with Lynch Syndrome, colorectal cancer and breast cancer. A family with this variant suggests lack of segregation with the disease since one of the affected family members did not carry the variant, although four affected family members did carry the variant (Genuardi_1999). One publication indicates the variant co-occurred with a "familial MMR mutation (MSH6)" (Jori_2015) while an additional co-occurrence with a pathogenic variant has been reported via internal testing (MSH2 c.1786_1788delAAT, p.Asn596del), providing supporting evidence for a benign role. Experimental evidence demonstrated no effect on splicing and transcript stability in lymphocytes from a carrier individual (Damaso_2020). Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and four ClinVar submitters (evaluation after 2014) cite it as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000659882 SCV001135744 uncertain significance Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000076286 SCV001450729 likely benign Lynch syndrome 2020-12-02 criteria provided, single submitter clinical testing The MSH2 c.1787A>G (p.Asn596Ser) missense change has a maximum subpopulation frequency of 0.054% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-47702191-A-G). This variant results in a conservative amino acid change and five of seven in silico tools predict a benign effect of this variant on protein function (BP4). To our knowledge, functional assays have not been performed. The variant has been identified in individuals with colorectal cancer or meeting Bethesda criteria of hereditary non-polyposis colorectal cancer (HPNCC; PMID: 18033691, 29212164, 16203774, 15849733), as well as individuals with unrelated phenotypes and no evidence of HPNCC (PMID: 22703879, 25637381, internal data). A family with this variant suggests lack of segregation since one of the affected family members did not carry the variant (BS4_Supporting; PMID: 10573010). Another report indicates that the variant co-occurred with a familial pathogenic MSH6 variant in one individual (BP2; PMID: 26517685). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS4_Supporting, BP2, BP4.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034554 SCV000043344 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
CSER _CC_NCGL, University of Washington RCV000148641 SCV000190356 uncertain significance Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000034554 SCV001550511 uncertain significance not provided no assertion criteria provided clinical testing The MSH2 p.Asn596Ser variant was identified in 6 of 6092 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer, breast cancer, and ovarian cancer and was not identified in 2712 control chromosomes from healthy individuals (Barnetson 2008, Genuardi 1999, Jalkh 2017, Pal 2012, Viel 1997, Woods 2005). The variant was also identified in the following databases: dbSNP (ID: rs41295288) as "With Uncertain significance allele", ClinVar (3x uncertain significance, including review by expert panel InSiGHT, 1x likely benign, 2x benign), Clinvitae, UMD-LSDB (2x, unclassified variant), Mismatch Repair Genes Variant Database, and the Insight Hereditary Tumors Database (12x, uncertain significance). The variant was not identified in COGR, Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 82 of 277212 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 7 of 24034 chromosomes (freq: 0.0003), Other in 7 of 6464 chromosomes (freq: 0.001), Latino in 18 of 34416 chromosomes (freq: 0.0005), European in 43 of 126708 chromosomes (freq: 0.0003), Ashkenazi Jewish in 3 of 10152 chromosomes (freq: 0.0003), and South Asian in 4 of 30780 chromosomes (freq: 0.0001). The variant was not observed in the East Asian or Finnish populations. Two studies have identified this variant in a proband from a family with affected family members (father and two paternal first cousins who carried this variant), but it was not present in another paternal first cousin who was diagnosed with CRC and endometrial cancer at 46 and 48 respectively (Genuardi 1999, Viel 1997). The p.Asn596 residue is conserved in mammals but not in more distantly related organisms. However four out of five 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.

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