2-47783232-G-T

Variant names:

• chr2-47783232-G-T
• rs374748889
• ENST00000445503.5:n.-2G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The ENST00000445503.5(MSH6):​n.-2G>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,611,176 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 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: MSH6 ENST00000445503.5 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:5
• Conservation: PhyloP100: 0.571
• Publications: 2 publications found

Genes affected

MSH6 (HGNC:7329): (mutS homolog 6) This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

MSH6 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, 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
• Muir-Torre syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• rhabdomyosarcoma

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 2-47783232-G-T is Benign according to our data. Variant chr2-47783232-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 142219.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.-2G>T		5_prime_UTR_variant	Exon 1 of 10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.-2G>T		5_prime_UTR_variant	Exon 1 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152214 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: 0.000578

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

GnomAD2 exomes AF: 0.0000123 AC: 3 AN: 244064 AF XY: 0.00000750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000561

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1458962 Hom.: 0 Cov.: 30 AF XY: 0.00000827 AC XY: 6 AN XY: 725858

African (AFR) AF: 0.00 AC: 0 AN: 33098

American (AMR) AF: 0.00 AC: 0 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39482

South Asian (SAS) AF: 0.00 AC: 0 AN: 86014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111324

Other (OTH) AF: 0.000249 AC: 15 AN: 60302

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

Asia WGS AF: 0.00260 AC: 9 AN: 3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:3

Aug 27, 2021

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the MSH6 gene demonstrated a homozygous sequence change in the 5’ UTR, c.-2G>T. This sequence change has been described in the gnomAD database with a frequency of 0.01% in the East Asian subpopulation (dbSNP rs374748889). This sequence change is not clearly predicted to have a deleterious effect on splicing based on in silico splice prediction programs. This change does not appear to have been previously described in individuals with MSH6-related disorders. The functional significance of this sequence change is not known at present and its contribution to this individual's disease phenotype cannot definitively be determined.

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 13, 2025

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: MSH6 c.-2G>T is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 1.2e-05 in 244064 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-2G>T has been reported in the literature (example, Liu_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26888055). ClinVar contains an entry for this variant (Variation ID: 142219). Based on the evidence outlined above, the variant was classified as uncertain significance.

Hereditary cancer-predisposing syndrome Benign:3

Jul 17, 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.

Nov 05, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 5' prime UTR variant NM_000179.3(MSH6):c.-2G>T has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.-2G>T variant is observed in 1/17,840 (0.0056%) alleles from individuals of gnomAD East Asian background in gnomAD. The c.-2G>T variant is novel (not in any individuals) in 1kG. The c.-2G>T variant is a UTR variant. For these reasons, this variant has been classified as Likely Benig

Apr 25, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

MSH6, EXON1, c.-2G>T, r.(spl)?, Heterozygous, Uncertain Significance The MSH6 c.-2G>T variant was not identified in the literature in an affected population. The variant was identified in dbSNP (ID: rs374748889 as “With other allele”) and ClinVar (classified as likely benign by GeneDx and classified as uncertain significance by Ambry Genetics, Invitae, COGR, Quest Diagnostics, and Integrated Genetics). The variant was not identified in Cosmic, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database or Insight Hereditary Tumors database. The variant was identified in control databases in 5 of 270534 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6350 chromosomes (freq: 0.0002), East Asian in 3 of 18528 chromosomes (freq: 0.0002), and South Asian in 1 of 30416 chromosomes (freq: 0.00003); it was not observed in the African, Latino, European Non-Finnish, Ashkenazi Jewish or Finnish populations. The variant was previously identified by our laboratory in 1 individual with endometrial and ovarian cancer as co-occurring with a pathogenic PMS2 variant (c.2500_2501delinsG, p.Met834Glyfs*17), increasing the likelihood that the MSH6 c.-2G>T variant does not have clinical significance. The variant is located in the MSH6 promoter region (Liu 2016), which could result in reduced gene expression but further study would be needed to confirm this. 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.

Jun 13, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in the 5' UTR promoter region of the MSH6 gene. It does not change the encoded amino acid sequence of the MSH6 protein. This variant has not been published in the literature and is present in population databases (rs374748889, 0.02%). ClinVar contains an entry for this variant (RCV000131214). In summary, this is a rare 5' non-coding change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

not provided Uncertain:1 Benign:1

Sep 27, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26888055)

Jan 26, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH6 c.-2G>T variant has been reported in the published literature in an individual with a family history of pancreatic cancer (PMID: 33939675 (2021)) and in a tumor sample from an individual with colorectal cancer (PMID: 34197922 (2021)). The frequency of this variant in the general population, 0.000015 (4/275398 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect MSH6 mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant.

Breast and/or ovarian cancer Uncertain:1

Jan 05, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Jun 13, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in the 5' UTR promoter region of the MSH6 gene. It does not change the encoded amino acid sequence of the MSH6 protein. This variant has not been published in the literature and is present in population databases (rs374748889, 0.02%). ClinVar contains an entry for this variant (RCV000131214). In summary, this is a rare 5' non-coding change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

MSH6-related disorder Benign:1

May 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	18
DANN	Benign	0.72
PhyloP100		0.57
PromoterAI		-0.12	Neutral
Mutation Taster		=300/0	polymorphism

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: rs374748889; hg19: chr2-48010371;