NM_000251.3:c.-3G>C

Variant names:

• chr2-47403189-G-C
• rs587779960
• NM_000251.3:c.-3G>C

Variant summary

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

The NM_000251.3(MSH2):​c.-3G>C variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.0000257 in 1,592,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: MSH2 NM_000251.3 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:3
• Conservation: PhyloP100: 4.19

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 (BayesDel_noAF=-0.35).
• BP6: Variant 2-47403189-G-C is Benign according to our data. Variant chr2-47403189-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127624.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.-3G>C		5_prime_UTR_variant	Exon 1 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146	c.-3G>C		5_prime_UTR_variant	Exon 1 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000188 AC: 4 AN: 212752 Hom.: 0 AF XY: 0.0000173 AC XY: 2 AN XY: 115598

Gnomad AFR exome AF: 0.000236

Gnomad AMR exome AF: 0.0000329

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000160 AC: 23 AN: 1440364 Hom.: 0 Cov.: 31 AF XY: 0.0000154 AC XY: 11 AN XY: 714588

Gnomad4 AFR exome AF: 0.000301

Gnomad4 AMR exome AF: 0.0000486

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: 0.00000544

Gnomad4 OTH exome AF: 0.0000838

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74388

Gnomad4 AFR AF: 0.000410

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.000140

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Oct 11, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 17, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH2 c.-3G>C is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 1.9e-05 in 212752 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-3G>C has been reported in the literature in individuals affected with Colorectal Cancer (Yurgelun_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variant(s) have been reported (MLH1 c.2070_2071insTT, p.I691Lfs), providing supporting evidence for a benign role (Yurgelun_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 127624). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Lynch syndrome Uncertain:2

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH2 c.-3G>C variant was not identified in the literature nor was it identified in the COGR, Cosmic, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or InSiGHT Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs587779960 as "With Uncertain significance allele") and ClinVar (5x as uncertain significance by GeneDx, Ambry Genetics, Counsyl, Color Genomics, and Integrated Genetics/Laboratory Corporation of America). The variant was identified in control databases in 8 of 238158 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 7 of 20486 chromosomes (freq: 0.0003) and Latino in 1 of 30410 chromosomes (freq: 0.00003); it was not observed in the Other, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The c.-3G>C variant is located in the kozak consensus sequence and typically a purine (adenine or guanine) is always observed at this position, increasing the likelihood this variant may have clinical significance. 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. -

Jan 11, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is located in the 5' untranslated region of the MSH2 gene. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 7/244138 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. -

Hereditary cancer-predisposing syndrome Uncertain:2

Sep 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-3G>C variant is located in the 5' untranslated region (5’ UTR) of the MSH2 gene. This variant results from a G to C substitution 3 bases upstream from the first translated codon. This nucleotide position is not well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Apr 17, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is located in the 5' untranslated region of the MSH2 gene. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 7/244138 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 Uncertain:1 Benign:1

Mar 29, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2024

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 27363726]. -

not provided Uncertain:1 Benign:1

Mar 22, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH2 c.-3G>C variant has not been reported in individuals with an MSH2 related cancer. However, this variant has been described in the Exome Aggregation Consortium (ExAC) in publication (PMID: 26888055 (2016)). The frequency of this variant in the general population, 0.00028 (6/21394 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -

Jun 23, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nucleotide substitution has no predicted effect on splicing and is not conserved across species; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533) -

MSH2-related disorder Uncertain:1

Jun 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH2 c.-3G>C variant is located in the 5' untranslated region. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127624/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs587779960; hg19: chr2-47630328;