2-47410109-C-G

Variant names:

• chr2-47410109-C-G
• rs145649774
• NM_000251.3:c.382C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS2

The NM_000251.3(MSH2):​c.382C>G​(p.Leu128Val) variant causes a missense change. The variant allele was found at a frequency of 0.000149 in 1,613,672 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L128R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:10 O:1
• Conservation: PhyloP100: 3.99
• Publications: 15 publications found

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]

MSH2 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 18 benign, 36 uncertain in NM_000251.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.15265647).
• BP6: Variant 2-47410109-C-G is Benign according to our data. Variant chr2-47410109-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127644.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.382C>G	p.Leu128Val	missense_variant	Exon 3 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.382C>G	p.Leu128Val	missense_variant	Exon 3 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152190 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000287 AC: 72 AN: 251092 AF XY: 0.000391

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000155 AC: 226 AN: 1461364 Hom.: 2 Cov.: 31 AF XY: 0.000219 AC XY: 159 AN XY: 726926

African (AFR) AF: 0.0000299 AC: 1 AN: 33466

American (AMR) AF: 0.0000671 AC: 3 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.00182 AC: 157 AN: 86132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000405 AC: 45 AN: 1111710

Other (OTH) AF: 0.000282 AC: 17 AN: 60362

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152308 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74476

African (AFR) AF: 0.00 AC: 0 AN: 41560

American (AMR) AF: 0.000131 AC: 2 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000354 AC: 43

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:10 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:2

Jun 22, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 11, 2017

True Health Diagnostics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 12, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 27, 2024

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:2

Sep 12, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 18, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27449771, 23047549, 23729658, 25479140) -

Apr 06, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1 Benign:1

Nov 26, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH2 c.382C>G (p.Leu128Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 121402 control chromosomes, predominantly at a frequency of 0.0018 within the South Asian subpopulation in the ExAC database. The observed variant frequency within South Asian control individuals in the ExAC database is approximately 3.2 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 South Asian origin. c.382C>G has been reported in the literature in individuals affected with a variety of cancers such as ovarian, pancreatic, breast, prostate (example, Pal_2012, Grant_2015, Amemiya_2015, Yang_2016). In one family with this variant, 1 transmission of the variant allele and 1 transmission of the reference allele to affected individuals was reported (Juhari_2018). These data suggest the variant of interest does not co-segregate with the disease. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.9097dupA, p.Thr3033fsX11), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and conflicting assessments (VUS, n=5, likely benign, n=5). Based on the evidence outlined above, the variant was classified as likely benign. -

Lynch syndrome 1 Uncertain:1 Benign:1

Sep 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Dec 04, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered 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: 27363726]. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Breast and/or ovarian cancer Benign:1

Mar 10, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer Benign:1

Sep 11, 2024

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

Endometrial carcinoma Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH2, p.Leu128Val variant was not identified in the literature. The p.Leu128Val variant was identified in dbSNP (ID: rs145649774) as “With Uncertain significance allele”, Clinvitae database (classified as VUS), MUTDB, ClinVar database (classified as uncertain significance, submitters: GeneDx, Ambry Genetics, Invitae), and UMD (1x with an “unclassified variant” classification).The p.Leu128Val variant was also identified in the NHLBI GO Exome Sequencing Project in 3 of 8600 European American alleles and 1 of 4406 African American alleles, and in the Exome Aggregation Consortium database (March 14, 2016) in 30 of 16512 chromosomes (frequency: 0.002) of South Asian individuals, 9 of 66732 (frequency: 0.00013) of European (Non-Finnish) individuals, 1 of 10404 (frequency: 9.61E-05) of African individuals, 1 of 11578 (frequency: 8.64E-05) of Latino individuals and 2 of 908 (frequency: 0.002) in other individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Leu128 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The p.Leu128Val 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. The observation of this variant with a co-occurring pathogenic variant (MLH1, EXON05-8, c.381-?_677del+?) by our laboratory increases the likelihood this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time but we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Lynch syndrome Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D;D;.;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.8	M;.;.;.;.
PhyloP100		4.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.4	N;D;N;.;N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0030	D;D;D;.;D
Sift4G	Uncertain	0.0060	D;D;D;.;D
Polyphen		0.37	B;.;.;.;P
Vest4		0.77
MVP		0.90
MPC		0.015
ClinPred		0.10	T
GERP RS		5.7
Varity_R		0.65
gMVP		0.61
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs145649774; hg19: chr2-47637248;