rs61756469

chr2-47783340-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BP6

The NM_000179.3(MSH6):c.107C>T(p.Ala36Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000702 in 1,610,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A36S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:10
• Conservation: PhyloP100: 0.976

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 17 uncertain in NM_000179.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.1876843).
• BP6: Variant 2-47783340-C-T is Benign according to our data. Variant chr2-47783340-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 140779.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Benign=2, Uncertain_significance=5}. Variant chr2-47783340-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.107C>T	p.Ala36Val	missense_variant	1/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.107C>T	p.Ala36Val	missense_variant	1/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152190 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: 0.000193

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: 37 AN: 235384 Hom.: 0 AF XY: 0.000146 AC XY: 19 AN XY: 129728

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.: 0 Cov.: 30 AF XY: 0.0000882 AC XY: 64 AN XY: 725342

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: 5 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74472

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.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000130 AC: 1

ExAC AF: 0.000152 AC: 18

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 22, 2023	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 18, 2021	- -
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. -
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	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 17, 2022	- -
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	GeneDx	Apr 26, 2021	This variant is associated with the following publications: (PMID: 26530882, 23621914, 29616133, 30132833) -

Lynch syndrome 5 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 18, 2016	- -
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]. -

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 condition 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 “With Uncertain significance allele”, 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, “Other” 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. -

not specified Benign:1

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. -

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

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.75	T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.78	T
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	T
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

Other links and lift over

dbSNP: rs61756469; hg19: chr2-48010479; COSMIC: COSV105861176; COSMIC: COSV105861176;