rs61756469

Positions:

chr2-47783340-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS2BP4

This summary comes from the ClinGen Evidence Repository: The MSH6 (NM_000179.3):c.107C>T is a missense variant predicted to cause substitution of Alanine to Valine at amino acid 36 (p.Ala36Val). The prior probability for pathogenicity of this missense variant is 0.04 according to http://priors.hci.utah.edu/PRIORS (BP4). The gnomAD v4.1 Grpmax AF is 0.0001535, not meeting BS1 criteria according to the Maximum Credible Allele Frequency (MCAF) cutoffs for MSH6. Co-occurrence with truncating variant MSH6 c.3202C>T (p.Arg1068*) in a patient with CRC and no signs of CMMR-D (BS2).In summary, this variant meets the criteria to be classified as LIKELY BENIGN for Lynch Syndrome, based on the MMR gene specific ACMG/AMP criteria established by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: BS2 and BP4 (VCEP specifications version 1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA007963/MONDO:0005835/138

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

MSH6
NM_001406799.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:11

Conservation

PhyloP100: 0.976

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 -5 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3 linkuse as main transcript	c.107C>T	p.Ala36Val	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.107C>T	p.Ala36Val	missense_variant	1/10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000157

AC:

AN:

235384

Hom.:

AF XY:

0.000146

AC XY:

AN XY:

129728

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.000912

Gnomad SAS exome

AF:

0.000267

Gnomad FIN exome

AF:

0.000377

Gnomad NFE exome

AF:

0.0000386

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000741

AC:

108

AN:

1458122

Hom.:

Cov.:

AF XY:

0.0000882

AC XY:

AN XY:

725342

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000154

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.000233

Gnomad4 FIN exome

AF:

0.000211

Gnomad4 NFE exome

AF:

0.0000504

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000671

Hom.:

Bravo

AF:

0.0000453

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000130

AC:

ExAC

AF:

0.000152

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 02, 2021	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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 19, 2020	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MSH6: BP1 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 17, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2021	This variant is associated with the following publications: (PMID: 26530882, 23621914, 29616133, 30132833) -

Lynch syndrome 5

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 29, 2023	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: 25085752]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 18, 2016	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 30, 2018	Variant summary: MSH6 c.107C>T (p.Ala36Val) results in a non-conservative amino acid change located outside of any known functional domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. An algorithm developed specifically to ascertain variants in MSH6 gene suggest that this missense change has no impact on MSH6 function (Terui_2013). The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 5.35 fold above the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The c.107C>T has been reported in the literature in two family members affected with familial non-medullary thyroid cancer without reported personal or family history of Lynch Syndrome; both individuals also carried in-frame variant in GNAS gene (Lu_2015). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 29, 2021

- -

MSH6-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 18, 2023

The MSH6 c.107C>T variant is predicted to result in the amino acid substitution p.Ala36Val. This variant has been reported in an individual with non-medullary thyroid cancer (Yu et al. 2015. PubMed ID: 26530882). This variant is reported in 0.084% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48010479-C-T) and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/140779/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Endometrial carcinoma

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MSH6 p.Ala36Val variant was identified in the literature however the frequency of this variant in an affected population was not provided (Terui_2013_23621914, Yu_2015_26530882). The variant was also identified in the following databases: dbSNP (ID: rs61756469) as â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (5x as uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl, Color Geomics) and Clinvitae (4x as uncertain significance). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database and Insight Hereditary Tumors Database. The variant was identified in control databases in 36 of 263104 chromosomes at a frequency of 0.00014 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 5 of 117454 chromosomes (freq: 0.000043), Ashkenazi Jewish in 1 of 9824 chromosomes (freq: 0.0001), East Asian in 14 of 18328 chromosomes (freq: 0.00076), European Finnish in 8 of 25266 chromosomes (freq: 0.0003), and South Asian in 8 of 30212 chromosomes (freq: 0.00026); while the variant was not observed in the African, â€šÃ„ÃºOtherâ€šÃ„Ã¹ and Latino, populations. The p.Ala36 residue is not conserved in mammals and 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. 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. 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. -

Hereditary nonpolyposis colon cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

Ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

.;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.75

T;T

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.69

N;N

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.71

N;N

REVEL

Benign

0.18

Sift

Benign

0.10

T;D

Sift4G

Benign

0.14

T;T

Polyphen

0.27

.;B

Vest4

0.35

MVP

0.87

ClinPred

0.078

GERP RS

3.6

Varity_R

0.13

gMVP

0.43

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