2-47783473-A-G

Position:

• chr2-47783473-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001406804.1(MSH6):​c.182+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000277 in 1,443,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: MSH6 NM_001406804.1 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: -0.0390

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-47783473-A-G is Benign according to our data. Variant chr2-47783473-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219856.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=1, Benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.240A>G	p.Val80Val	synonymous_variant	1/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.240A>G	p.Val80Val	synonymous_variant	1/10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151742 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000442

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000511 AC: 3 AN: 58704 Hom.: 0 AF XY: 0.0000629 AC XY: 2 AN XY: 31802

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000118

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: 0.0000835

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000271 AC: 35 AN: 1291758 Hom.: 0 Cov.: 34 AF XY: 0.0000239 AC XY: 15 AN XY: 628444

Gnomad4 AFR exome AF: 0.000118

Gnomad4 AMR exome AF: 0.000155

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000157

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000262

Gnomad4 OTH exome AF: 0.0000188

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151742 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74116

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.0000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lynch syndrome 5 Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 28, 2023	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Sep 19, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 17, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Lynch syndrome Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MSH6 p.Val80= variant was not identified in the literature nor was it identified in COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs864622281) as “With Likely benign allele”, in ClinVar (classified likely benign by Invitae, Counsyl and Ambry Genetics and uncertain significance by Laboratory Corporation of America), Clinvitae (2x) and the Genome Aggregation Database (Feb 27, 2017) in 2 of 30730 control chromosomes (frequency: 0.00007). It was observed in the following populations: African in 1 of 8664 chromosomes (frequency: 0.0001) and European Non-Finnish in 1 of 14844 chromosomes (frequency: 0.00007), but not in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish and South Asian populations. The p.Val80= variant is not expected to have clinical significance because it does not result in a change of amino acid. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 24, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 12, 2015	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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 29, 2019

- -

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
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.5
DANN	Benign	0.55

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: rs864622281; hg19: chr2-48010612;