rs63749910

chr2-47471033-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3 BP6_Very_Strong

The NM_000251.3(MSH2):c.1730T>C(p.Ile577Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,564,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I577V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:8 B:15
• Conservation: PhyloP100: 7.38

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84
• BP6: Variant 2-47471033-T-C is Benign according to our data. Variant chr2-47471033-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 41644.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47471033-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1730T>C	p.Ile577Thr	missense_variant	11/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1730T>C	p.Ile577Thr	missense_variant	11/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000139 AC: 35 AN: 250898 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135694

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000221 AC: 312 AN: 1411896 Hom.: 0 Cov.: 25 AF XY: 0.000203 AC XY: 143 AN XY: 705500

Gnomad4 AFR exome AF: 0.0000308

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000282

Gnomad4 OTH exome AF: 0.000136

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74366

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000269 Hom.: 0

Bravo AF: 0.000196

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000327

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:8 Benign:15

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:3 Benign:6

Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2020	This variant is associated with the following publications: (PMID: 27958275, 22703879, 16636019, 19117025, 22006311, 16736289, 16885385, 21056691, 25871441, 16408224, 26878173, 26182300) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 18, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MSH2 p.Ile577Thr variant was identified in 6 of 1950 proband chromosomes (frequency: 0.003) from individuals or families with endometrial, colorectal, and ovarian cancer (Hampel 2006, Limburg 2011, South 2009, Spaepen 2006, Walsh 2011), and was present in 1 of 1142 control chromosomes (frequency: 0.0009) from healthy individuals (Johnston 2012). The variant was also identified in dbSNP (ID: rs63749910) as “With Uncertain significance allele”, ClinVar (as likely benign, reviewed by expert panel and Ambry Genetics, and as uncertain significance by GeneDx, Invitae, Knight Diagnostics, Laboratory for Molecular Medicine, Quest Diagnostics, Integrated Genetics, and Biesecker Lab), Clinvitae (6x), UMD-LSDB (1x as uncertain significance), Insight Colon Cancer Gene Variant Database (5x as "class 2 likely not pathogenic"), and Mismatch Repair Genes Variant Database (1x). The variant was not identified in COGR, Cosmic, MutDB, or Zhejiang University Database. The variant was identified in control databases in 41 of 276890 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24008 chromosomes (freq: 0.00008), Other in 1 of 6458 chromosomes (freq: 0.0002), Latino in 1 of 34416 chromosomes (freq: 0.00003), and European (Non-Finnish) in 37 of 126452 chromosomes (freq: 0.0003); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. One study reported the variant was found to co-occur with a pathogenic MUTYH variant: c.36+1G>A (Niessen 2006). The p.Ile577 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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 the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 25, 2017	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Classified within the last year. This variant has been reported in 1 indidivual who did not have cancer, and 1 individual with CRC. The variant has a Max MAF of 0.02% in ExAC (14 alleles) and 0.03% in gnomAD (38 alleles). It is classified with 3 stars in ClinVar as Likely benign by an expert panel (InSiGHT) and Ambry, and VUS by GeneDx, Invitae, and Biesecker lab. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 16, 2019	DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.1730T>C, in exon 11 that results in an amino acid change, p.Ile577Thr. This sequence change has been described previously in individuals with colorectal cancer, ovarian cancer or adenocarcinoma of the endometrium (PMID: 21056691, PMID: 19117025, PMID: 16885385, PMID: 16736289). It has been described in the gnomAD database with a low population frequency of 0.029% in non-Finnish European subpopulation (dbSNP rs63749910). The p.Ile577Thr change affects a moderately conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Ile577Thr substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these evidences and the lack of functional studies, the clinical significance of the p.Ile577Thr change remains unknown at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2021	Variant summary: MSH2 c.1730T>C (p.Ile577Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251570 control chromosomes, predominantly at a frequency of 0.00028 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (0.00015 vs 0.00057), allowing no conclusion about variant significance. c.1730T>C has been reported in the literature in individuals affected with colorectal cancer, endometrial cancer, ovarian cancer and hereditary diffuse gastric cancer (Spaepen_2006, Niessen_2006, Limburg_2011, Hampel_2006, South_2009, Hansford_2015) without strong evidence of causality. Many of these tumors show normal MSH2 expression by immunohistochemistry. In one patient absence of MLH1 (but normal expression of MSH2) protein was seen together with methylation of MLH1 promoter region suggestive of an alternative etiology and molecular basis of disease in this patient (Hampel_2006). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At-least two co-occurrences with other pathogenic variant(s) have been reported in the literature and also observed at our laboratory ( MUTYH c.36+1G>A, Niessen_2006; BRCA1 c.3005delA , p.Asn1002fsX22 at our laboratory), providing supporting evidence for a benign role. A study that computed a tumor characteristic likelihood ratio (TCLR) in combination with in-silico predictors and multifactorial variant prediction (MVP) model including allele frequency, co-occurrence, co-segregation, clinical and family history information classified this variant a benign (Li_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine 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 (likely benign/benign, n=4; VUS, n=5). Based on the evidence outlined above, the variant was classified as benign. -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 19, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 20, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2022	- -

Lynch syndrome 1 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 30, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 16, 2019	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 02, 2021

- -

MSH2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 12, 2021

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). -

Hereditary nonpolyposis colon cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

Lynch syndrome Benign:1

Likely benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Multifactorial likelihood analysis posterior probability 0.001-0.049 -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.7	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.6	D;D;.;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0030	D;D;.;D
Sift4G	Uncertain	0.0070	D;D;.;D
Polyphen		0.92	P;.;.;P
Vest4		0.94
MVP		0.98
MPC		0.016
ClinPred		0.45	T
GERP RS		5.9
Varity_R		0.69
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs63749910; hg19: chr2-47698172; COSMIC: COSV51886801;