2-47783271-A-T

Position:

• chr2-47783271-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001406804.1(MSH6):​c.-18A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH6 NM_001406804.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.35

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.38A>T	p.Lys13Met	missense_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.38A>T	p.Lys13Met	missense_variant	1/10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 02, 2023

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 455305). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 13 of the MSH6 protein (p.Lys13Met). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2017

The p.K13M variant (also known as c.38A>T), located in coding exon 1 of the MSH6 gene, results from an A to T substitution at nucleotide position 38. The lysine at codon 13 is replaced by methionine, an amino acid with similar properties. An alteration at the same codon, c.38A>C (p.K13T), has been reported in one of 932 colorectal cancer patients diagnosed under 55 years of age and was not seen in any of the 1104 control individuals; however this individual’s tumor showed microsatellite stability and presence of MSH6 staining on immunohistochemistry and was therefore classified as "Undefined" (Barnetson RA et al, Hum. Mutat. 2008 Mar; 29(3):367-74). The p.K13M variant amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. However, the CoDP in silico tool predicts this alteration to have minor impact on molecular function, with a score of 0.001 (Terui H et al. J. Biomed. Sci. 2013 Apr;20:25). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	.;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.81	T;T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	0.81	L;L;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.7	D;N;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0060	D;D;.
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.99	.;D;.
Vest4		0.49
MutPred		0.25		Loss of methylation at K13 (P = 0.0026);Loss of methylation at K13 (P = 0.0026);Loss of methylation at K13 (P = 0.0026);
MVP		0.92
ClinPred		0.88	D
GERP RS		3.4
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.60
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs41294988; hg19: chr2-48010410;