rs549467183

chr2-47475228-G-Achr2-47475228-G-Cchr2-47475228-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BP6_Strong

The NM_000251.3(MSH2):c.1963G>A(p.Val655Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000379 in 1,611,410 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V655A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (1 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4 B:8
• Conservation: PhyloP100: 1.40

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 Likely_benign. Variant got -6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 16 uncertain in NM_000251.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.04226145).
• BP6: Variant 2-47475228-G-A is Benign according to our data. Variant chr2-47475228-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 127637.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=5, Benign=3}. Variant chr2-47475228-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1963G>A	p.Val655Ile	missense_variant	12/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1963G>A	p.Val655Ile	missense_variant	12/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000397 AC: 6 AN: 151208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000264

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000131 AC: 33 AN: 251324 Hom.: 1 AF XY: 0.000103 AC XY: 14 AN XY: 135832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000377 AC: 55 AN: 1460122 Hom.: 1 Cov.: 33 AF XY: 0.0000372 AC XY: 27 AN XY: 726324

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000694

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000397 AC: 6 AN: 151288 Hom.: 0 Cov.: 32 AF XY: 0.0000406 AC XY: 3 AN XY: 73832

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000264

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000418

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000529

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 21, 2023	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Uncertain significance, reviewed by expert panel	curation	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Jun 13, 2018	MLH1 methylation, but tumour with all proteins absent by IHC, proficient in CIMRA -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jan 04, 2018	- -

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 10, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 06, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2021	This variant is associated with the following publications: (PMID: 26845104, 28767289, 25186627, 30212499, 30262796, 33294277, 32659497, 31569399) -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 14, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 23, 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. -

Lynch syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

Nov 20, 2015

- -

Mismatch repair cancer syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jul 09, 2020

The homozygous p.Val655Ile missense variant identified in MSH2 has been reported in the literature in individuals affected with pancreatic ductal adenocarcinoma [PMID: 28767289] and breast and ovarian cancer syndrome [PMID: 30262796]. The variant has been reported in ClinVar by multiple independent sources with conflicting interpretations about its pathogenicity [classified as benign, likely benign, and a variant of uncertain significance. Variation ID: 127637]. The p.Val655Ile variant is classified as a variant of uncertain significance by the ClinVar/ClinGen expert panel [Variation ID:127637]. The variant has 0.00003510 allele frequency in the gnomAD(v3) database (5 out of 142,452 heterozygous alleles), and 0.0001313 allele frequency in the “Exome subset” of gnomAD(v2) database (33 out of 251,324 heterozygous alleles, 1 homozygote). The affected residue is not well conserved. In Silico prediction tools provide conflicting interpretations about potential pathogenicity of this variant. Based on the current evidence, the p.Val655Ile variant in the MSH2 gene is assessed as a variant of uncertain significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 12, 2022

Variant summary: MSH2 c.1963G>A (p.Val655Ile) results in a conservative amino acid change in 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 0.00013 in 251324 control chromosomes, predominantly at a frequency of 0.00075 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is higher than the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1963G>A has been reported in the literature in sequencing studies among individuals affected with breast, colorectal and pancreatic cancers (example, Shirts_2016, Tung_2015, Shindo_2017). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported in the literature and at our laboratory (BRCA1 del exons 9-12, Tung_2015; ATM c.8264_8268delATAAG, p.Tyr2755fs*12, Internal testing data), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories and one expert panel (InSIGHT) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters have reported the variant with conflicting assessments (6 as benign/likely benign and 4 as a VUS). Based on the evidence outlined above, the variant was classified as benign. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	17
Dann	Benign	0.88
DEOGEN2	Benign	0.39	T;.;.;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.042	T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.66	N;.;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.46	N;N;.;N
REVEL	Uncertain	0.36
Sift	Benign	0.25	T;T;.;T
Sift4G	Benign	0.41	T;T;.;T
Polyphen		0.028	B;.;.;B
Vest4		0.45
MutPred		0.57		Loss of phosphorylation at Y656 (P = 0.1133);.;Loss of phosphorylation at Y656 (P = 0.1133);Loss of phosphorylation at Y656 (P = 0.1133);
MVP		0.79
MPC		0.0075
ClinPred		0.025	T
GERP RS		2.8
Varity_R		0.039
gMVP		0.39

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: rs549467183; hg19: chr2-47702367; COSMIC: COSV99028391; COSMIC: COSV99028391;