rs63750691

Variant names:

• chr3-37017521-C-G
• rs63750691
• NM_000249.4:c.806C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-37017521-C-G
• chr3-37017521-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000249.4(MLH1):​c.806C>G​(p.Ser269*) variant causes a stop gained change involving the alteration of a 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 Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 NM_000249.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 7.59

Genes affected

MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 18 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
• PP5: Variant 3-37017521-C-G is Pathogenic according to our data. Variant chr3-37017521-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 17098.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37017521-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.806C>G	p.Ser269*	stop_gained	Exon 10 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.806C>G	p.Ser269*	stop_gained	Exon 10 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1

Dec 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Lynch syndrome Pathogenic:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Coding sequence variation resulting in a stop codon -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

May 15, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant has been observed in several individuals and families affected with Lynch syndrome (PMID: 15571801, 12547705, 18625694, 17453009, 9311737). ClinVar contains an entry for this variant (Variation ID: 17098). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser269*) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 13, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S269* pathogenic mutation (also known as c.806C>G), located in coding exon 10 of the MLH1 gene, results from a C to G substitution at nucleotide position 806. This changes the amino acid from a serine to a stop codon within coding exon 10. This mutation has been identified in multiple individuals diagnosed with HNPCC/Lynch syndrome (Wijnen J et al. Am. J. Hum. Genet. 1997 Aug;61:329-35; Hendriks Y et al. Am. J. Pathol. 2003 Feb;162:469-77; Overbeek LI et al. Br. J. Cancer 2007 May;96:1605-12), including several patients whose tumors demonstrated high microsatellite instability and loss of MLH1 staining on immunohistochemistry (IHC) (van Puijenbroek M et al. Fam. Cancer 2008 Apr;7:319-30; Bosse T et al. Mod Pathol, 2013 Nov;26:1525-35; Post CCB et al. J Natl Cancer Inst, 2021 Mar). This mutation has also been reported as homozygous in a patient with colon cancer diagnosed at age 22 (Rey JM et al. Cancer Genet Cytogenet, 2004 Dec;155:149-51). Of note, this alteration is also designated as 269 TCA>TGA, S269X, and p.Ser269X in published literature. In addition to the clinical data presented in the literature, 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. -

Colon cancer Pathogenic:1

Feb 10, 2018

3DMed Clinical Laboratory Inc

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.98
ClinPred		1.0	D
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs63750691; hg19: chr3-37059012;