rs1428717797

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong

The NM_000179.3(MSH6):​c.236C>A​(p.Ser79Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000773 in 1,294,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S79S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

MSH6
NM_000179.3 stop_gained

Scores

1
1
5

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 2.82
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 2-47783469-C-A is Pathogenic according to our data. Variant chr2-47783469-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2567456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MSH6NM_000179.3 linkuse as main transcriptc.236C>A p.Ser79Ter stop_gained 1/10 ENST00000234420.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MSH6ENST00000234420.11 linkuse as main transcriptc.236C>A p.Ser79Ter stop_gained 1/101 NM_000179.3 P4P52701-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.73e-7
AC:
1
AN:
1294204
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
630034
show subpopulations
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:
9.69e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Lynch syndrome 5 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Aug 09, 2023This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsApr 19, 2023The p.S79* pathogenic mutation (also known as c.236C>A), located in coding exon 1 of the MSH6 gene, results from a C to A substitution at nucleotide position 236. This changes the amino acid from a serine to a stop codon within coding exon 1. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.020
CADD
Pathogenic
41
DANN
Benign
0.97
Eigen
Benign
-0.13
Eigen_PC
Benign
-0.50
FATHMM_MKL
Benign
0.032
N
MutationTaster
Benign
1.0
A;A
Vest4
0.60
GERP RS
0.38
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.72
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.72
Position offset: 1

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-48010608; COSMIC: COSV52287661; COSMIC: COSV52287661; API