2-47783421-C-T

Variant names:

• chr2-47783421-C-T
• rs587779920
• NM_000179.3:c.188C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000179.3(MSH6):​c.188C>T​(p.Ser63Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000737 in 1,357,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S63P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.159
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2793237).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.188C>T	p.Ser63Phe	missense_variant	Exon 1 of 10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.188C>T	p.Ser63Phe	missense_variant	Exon 1 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.37e-7 AC: 1 AN: 1357164 Hom.: 0 Cov.: 34 AF XY: 0.00000150 AC XY: 1 AN XY: 667860

African (AFR) AF: 0.00 AC: 0 AN: 28206

American (AMR) AF: 0.00 AC: 0 AN: 27324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22442

East Asian (EAS) AF: 0.00 AC: 0 AN: 33836

South Asian (SAS) AF: 0.00 AC: 0 AN: 74198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5454

European-Non Finnish (NFE) AF: 9.41e-7 AC: 1 AN: 1063012

Other (OTH) AF: 0.00 AC: 0 AN: 55768

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Sep 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 63 of the MSH6 protein (p.Ser63Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 1053294). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MSH6 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;T;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.78	T;T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.81	L;L;.
PhyloP100		0.16
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.77	N;N;.
REVEL	Benign	0.20
Sift	Uncertain	0.029	D;D;.
Sift4G	Uncertain	0.057	T;D;D
Polyphen		0.38	.;B;.
Vest4		0.22
MutPred		0.17		Loss of phosphorylation at S63 (P = 0.0092);Loss of phosphorylation at S63 (P = 0.0092);.;
MVP		0.82
ClinPred		0.19	T
GERP RS		2.6
PromoterAI		-0.073	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.082
gMVP		0.36
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs587779920; hg19: chr2-48010560; COSMIC: COSV52275784; COSMIC: COSV52275784;