2-47783306-G-T

Position:

chr2-47783306-G-T

Variant summary

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

The NM_000179.3(MSH6):c.73G>T(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: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:12

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]

MSH6 links:

MSH6 (HGNC:):

MSH6 links:

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: {Likely_benign=12, Uncertain_significance=3}. 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/exons	MANE	Protein	UniProt
MSH6	NM_000179.3 linkuse as main transcript	c.73G>T	p.Ala25Ser	missense_variant	1/10	ENST00000234420.11	NP_000170.1	P52701-1Q3SWU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 linkuse as main transcript	c.73G>T	p.Ala25Ser	missense_variant	1/10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152176

Hom.:

Cov.:

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:

AN:

242354

Hom.:

AF XY:

0.000143

AC XY:

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.:

Cov.:

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:

AN:

152176

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

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.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000235

AC:

ExAC

AF:

0.000150

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 25, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 05, 2023	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. -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 07, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 19, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 16, 2019	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

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MSH6: BP1, BP2, BS3:Supporting -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 10, 2018	- -

MSH6-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 22, 2024

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 (Jóri 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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Nov 14, 2023

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

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

LIST_S2

Benign

0.51

T;T;T

M_CAP

Pathogenic

0.88

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.69

N;N;.

PrimateAI

Uncertain

0.72

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over