rs587779239

chr2-47783474-G-Achr2-47783474-G-Cchr2-47783474-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1 BP4_Moderate BP6_Very_Strong

The NM_000179.3(MSH6):c.241G>A(p.Ala81Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000832 in 1,442,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A81V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000085 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:5
• Conservation: PhyloP100: 1.46

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 Benign. Variant got -8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 16 uncertain in NM_000179.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.230622).
• BP6: Variant 2-47783474-G-A is Benign according to our data. Variant chr2-47783474-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 89282.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47783474-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.241G>A	p.Ala81Thr	missense_variant	1/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.241G>A	p.Ala81Thr	missense_variant	1/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000852 AC: 11 AN: 1290728 Hom.: 0 Cov.: 34 AF XY: 0.0000112 AC XY: 7 AN XY: 627736

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000107

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74296

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2019	Not observed at a significant frequency in large population cohorts (Lek 2016); While protein-based in silico analysis supports that this variant does not alter protein structure/function, splice predictors suggest this variant may impact gene splicing. In the absence of RNA or functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge; Variant reported as benign or likely benign by a well-established clinical consortium and/or database (Thompson 2014); This variant is associated with the following publications: (PMID: 23104009, 26552419, 23621914, 22290698, 30212499) -

Lynch syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	- -
Likely benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Multifactorial likelihood analysis posterior probability 0.001-0.049 -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 24, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 06, 2016	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 03, 2017

Variant summary: The MSH6 c.241G>A (p.Ala81Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/30778 control chromosomes in gnomAD at a frequency of 0.0000325, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS). -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	21
Dann	Benign	0.96
DEOGEN2	Benign	0.24	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.61	T;T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.080	N;.
REVEL	Benign	0.18
Sift	Benign	0.075	T;.
Sift4G	Benign	0.47	T;T
Polyphen		0.0	B;.
Vest4		0.10
MVP		0.67
ClinPred		0.047	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.041
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.64		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587779239; hg19: chr2-48010613;