NM_000179.3:c.73G>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000179.3(MSH6):โ€‹c.73G>Tโ€‹(p.Ala25Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,611,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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: ๐‘“ 0.00021 ( 0 hom., cov: 33)
Exomes ๐‘“: 0.00017 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

1
1
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:13

Conservation

PhyloP100: -0.0360
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.14938664).
BP6
Variant 2-47783306-G-T is Benign according to our data. Variant chr2-47783306-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 89562.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=13}. Variant chr2-47783306-G-T is described in Lovd as [Likely_benign]. Variant chr2-47783306-G-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MSH6NM_000179.3 linkc.73G>T p.Ala25Ser missense_variant Exon 1 of 10 ENST00000234420.11 NP_000170.1 P52701-1Q3SWU9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MSH6ENST00000234420.11 linkc.73G>T p.Ala25Ser missense_variant Exon 1 of 10 1 NM_000179.3 ENSP00000234420.5 P52701-1

Frequencies

GnomAD3 genomes
AF:
0.000210
AC:
32
AN:
152176
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.000397
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.000140
AC:
34
AN:
242354
Hom.:
0
AF XY:
0.000143
AC XY:
19
AN XY:
132896
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000291
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:
0.000288
Gnomad OTH exome
AF:
0.000334
GnomAD4 exome
AF:
0.000170
AC:
248
AN:
1459666
Hom.:
0
Cov.:
30
AF XY:
0.000162
AC XY:
118
AN XY:
726168
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000448
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000383
Gnomad4 NFE exome
AF:
0.000211
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.000210
AC:
32
AN:
152176
Hom.:
0
Cov.:
33
AF XY:
0.000161
AC XY:
12
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.000397
Gnomad4 OTH
AF:
0.00144
Alfa
AF:
0.000312
Hom.:
0
Bravo
AF:
0.000181
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000235
AC:
2
ExAC
AF:
0.000150
AC:
18
EpiCase
AF:
0.000327
EpiControl
AF:
0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:13
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:4
Feb 06, 2020
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 14, 2017
GeneDx
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 criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jan 25, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in HGMD, classified as DM?. It has been seen in 2 breast cancer families. In one in vitro study the variant was shown to be mismatch repair proficient. In another paper it is predicted to be neutral. The variant has a Max MAF of 0.03% in ExAC (16 alleles) and 0.03% in gnomAD (35 alleles). It is classified with 3 stars in ClinVar as VUS by an expert panel (InSiGHT) and U Wash, and as Likely benign by GeneDx, Invitae, and Ambry. This region is not conserved and 2 mammals have a Ser at this position. -

Jun 05, 2023
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: MSH6 c.73G>T (p.Ala25Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 242354 control chromosomes, predominantly at a frequency of 0.00029 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.73G>T has been reported in the literature in individuals evaluated for Hereditary Nonpolyposis Colorectal Cancer (e.g. Nilbert_2009, Jori_2015, Houlleberghs_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrence with another potentially pathogenic variant has been reported at least twice (MSH6 c.2926_2929dupCGTT in Jori_2015 and MSH6 c.3103C>T/p.Arg1035X internal testing), providing supporting evidence for a benign role. The variant has also been reported in individuals with other cancer phenotypes (e.g. Wasielewski_2009, Shindo_2017) and healthy controls (e.g. Wasielewski_2009). At least two independent publications report experimental evidence that the variant does not affect normal function of MSH6 (e.g. Drost_2011, Houlleberghs_2017). The following publications have been ascertained in the context of this evaluation (PMID: 35904628, 22102614, 34445333, 28531214, 26517685, 18566915, 28767289, 19924528). Eleven other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=3) or likely benign (n=8). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:3
Jun 06, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

MSH6: BP1, BP2, BS3:Supporting -

Sep 10, 2018
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:3
Apr 07, 2015
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 19, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Jan 16, 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. -

Lynch syndrome Uncertain:1Benign:1
Nov 20, 2015
University of Washington Department of Laboratory Medicine, University of Washington
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 30, 2024
All of Us Research Program, National Institutes of Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

MSH6-related disorder Uncertain:1
Aug 22, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The MSH6 c.73G>T variant is predicted to result in the amino acid substitution p.Ala25Ser. This variant has been seen in individuals with breast or colorectal cancer (Nilbert et al. 2008. PubMed ID: 18566915; Wasielewski et al. 2009. PubMed ID: 19924528; Table S1 - Shirts et al. 2016. PubMed ID: 26845104; Table S2 - Houlleberghs et al. 2017. PubMed ID: 28531214), and an individual with pancreatic ductal adenocarcinoma and a family history of breast cancer (Shindo et al. 2017. PubMed ID: 28767289). In an individual with endometrial cancer this variant was detected with a different pathogenic variant in MSH6 (Jรณri et al. 2015. PubMed ID: 26517685). Functional studies indicate this variant does not impact MSH6 function (Drost et al. 2012. PubMed ID: 22102614; Table S2 - Houlleberghs et al. 2017. PubMed ID: 28531214). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/89562/). Although we suspect this variant is benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Endometrial carcinoma;C1833477:Lynch syndrome 5;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1
Jan 19, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:1
Nov 14, 2023
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

REVEL: 0.076 (BP4), approximately 2-fold of the estimated maximal expected allele (BS1_sup), BS3, PMID: 28531214: not identified as MMR abrogating. According to the ACMG standard criteria we chose these criteria: BP4 (supporting benign): REVEL: 0.076 (BP4), , BS1 (supporting benign): The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype, BS3 (strong benign): PMID: 28531214: not identified as MMR abrogating PMID: 22102614: In vitro MMR + -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
5.1
DANN
Benign
0.81
DEOGEN2
Benign
0.23
.;T;T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.013
N
LIST_S2
Benign
0.51
T;T;T
M_CAP
Pathogenic
0.88
D
MetaRNN
Benign
0.15
T;T;T
MetaSVM
Benign
-0.83
T
MutationAssessor
Benign
0.69
N;N;.
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
0.46
N;N;.
REVEL
Benign
0.076
Sift
Benign
0.22
T;T;.
Sift4G
Benign
0.93
T;T;T
Polyphen
0.041
.;B;.
Vest4
0.15
MVP
0.48
ClinPred
0.018
T
GERP RS
0.56
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.1
Varity_R
0.058
gMVP
0.48

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs267608026; hg19: chr2-48010445; API