2-47482945-C-T

Variant names:

• chr2-47482945-C-T
• rs587779969
• NM_000251.3:c.2801C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000251.3(MSH2):​c.2801C>T​(p.Thr934Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,610,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:5
• Conservation: PhyloP100: 1.48

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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12345126).
• BP6: Variant 2-47482945-C-T is Benign according to our data. Variant chr2-47482945-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127641.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2801C>T	p.Thr934Met	missense_variant	Exon 16 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2801C>T	p.Thr934Met	missense_variant	Exon 16 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000566 AC: 14 AN: 247562 Hom.: 0 AF XY: 0.0000596 AC XY: 8 AN XY: 134218

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000996

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000626

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000350 AC: 51 AN: 1458372 Hom.: 0 Cov.: 31 AF XY: 0.0000441 AC XY: 32 AN XY: 725330

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000584

Gnomad4 FIN exome AF: 0.0000564

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74294

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Jun 28, 2018

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. -

May 05, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 29, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with methionine at codon 934 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer, ovarian cancer, gastrointestinal stromal tumor and unspecified cancer (PMID: 19117025, 26898890, 27498913, 29596542, 31391288, 31569399) with some tumors exhibiting proficient mismatch repair abilities (PMID: 29596542, 31391288). This variant has been reported to occur in affected individuals together with another disease-causing variant in the MLH1 or MSH2 gene that could explain the observed phenotype (ClinVar variation ID: 127641). This variant has been identified in 14/247562 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:1 Benign:1

Nov 25, 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.2801C>T (p.Thr934Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.7e-05 in 247562 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (5.7e-05 vs 0.00057), allowing no conclusion about variant significance. c.2801C>T has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with HBOC, colorectal cancer in addition to an individual referred for genetic testing (example, Caminsky_2016, Hampel_2018, Mu_2016, South_2009, Wu_2019). 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 UMD database (MLH1 c.2252_2253del, p.Lys751SerfsX3; MSH2 c.1661+1G>T), providing supporting evidence for a benign role. One of these individuals who harbors the co-occuring causal variant in MLH1 is reported as having mismatch repair (MMR) function in tumor cells as MLH1 negative and MSH2 positive which is consistent with the observed variant spectrum. To our knowledge, no other experimental evidence demonstrating an impact on protein function has been reported. Six 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, n=4; VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:1

May 04, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29596542, 31391288, 26898890, 27720647, 19117025, 27498913, 31569399) -

Aug 30, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH2 c.2801C>T (p.Thr934Met) variant has been reported in the published literature in individuals affected with breast cancer and ovarian cancer (PMIDs: 19117025 (2009), 26898890 (2016), 31569399 (2019)), as well as in individuals referred for multigene hereditary cancer panel testing (PMID: 27720647 (2016)). It has also been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)). The frequency of this variant in the general population, 0.0001 (3/30122 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Carcinoma of colon Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH2 p.Thr934Met variant was identified in 2 of 728 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome and ovarian cancer (Caminsky 2016, South 2009). The variant was also identified in the following databases: dbSNP (ID: rs587779969 as “With Uncertain significance allele”), ClinVar (1x as likely benign by Invitae and 3x uncertain significance by GeneDx, Ambry Genetics, and Color Genomics), UMD-LSDB (5x as neutral), Insight Colon Cancer Gene Variant Database, and Insight Hereditary Tumors Database. The variant was not identified in the COGR, Cosmic, MutDB, Zhejiang University Database, or Mismatch Repair Genes Variant Database. The variant was identified in control databases in 14 of 243082 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 14858 chromosomes (freq: 0.0001), Latino in 1 of 33348 chromosomes (freq: 0.00003), European (Non-Finnish) in 7 of 110080 chromosomes (freq: 0.00006), Finnish in 1 of 22236 chromosomes (freq: 0.00005), and South Asian in 3 of 30260 chromosomes (freq: 0.0001); it was not observed in the Other, Ashkenazi Jewish, or East Asian populations. The variant was identified in our lab with a co-occurring pathogenic PMS2 variant (p.Gln719Argfs*6) increasing the likelihood that the p.Thr934Met variant does not have clinical significance. 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. The p.Thr934 residue is not conserved in mammals and four out of five 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. 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. -

Lynch syndrome Uncertain:1

Mar 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with methionine at codon 934 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer, ovarian cancer, gastrointestinal stromal tumor and unspecified cancer (PMID: 19117025, 26898890, 27498913, 29596542, 31391288, 31569399) with some tumors exhibiting proficient mismatch repair abilities (PMID: 29596542, 31391288). This variant has been reported to occur in affected individuals together with another disease-causing variant in the MLH1 or MSH2 gene that could explain the observed phenotype (ClinVar variation ID: 127641). This variant has been identified in 14/247562 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Lynch syndrome 1 Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.088	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.80	N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.021	B;.
Vest4		0.083
MutPred		0.36		Gain of stability (P = 0.0106);.;
MVP		0.71
MPC		0.016
ClinPred		0.057	T
GERP RS		3.8
Varity_R		0.030
gMVP		0.36

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: rs587779969; hg19: chr2-47710084;