rs267607727

Variant names:

• chr3-37001049-G-A
• rs267607727
• ENST00000458205:c.-422G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-37001049-G-A
• chr3-37001049-G-C
• chr3-37001049-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001167618.3(MLH1):​c.-422G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,370 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 Likely pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MLH1 NM_001167618.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 9.42

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.48
• PP5: Variant 3-37001049-G-A is Pathogenic according to our data. Variant chr3-37001049-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 90138.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37001049-G-A is described in Lovd as [Likely_pathogenic]. Variant chr3-37001049-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.302G>A	p.Gly101Asp	missense_variant	Exon 3 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.302G>A	p.Gly101Asp	missense_variant	Exon 3 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440370 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 717924

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1

Jul 12, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 23403630]. This variant is expected to disrupt protein structure [PMID: 26249686, Myriad internal data]. -

Lynch syndrome 1 Pathogenic:1

Mar 09, 2018

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Class 4 - Likely Pathogenic Classification using multifactorial probability: 0.968 -

not provided Pathogenic:1

Feb 02, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: reduced protein expression and MMR repair activity compared to wild type (Ellison 2004, Hinrichsen 2013); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with personal and/or family histories consistent with Lynch syndrome (Taylor 2003, Tournier 2008); This variant is associated with the following publications: (PMID: 19224586, 15475387, 23403630, 22290698, 25525159, 14635101, 18561205, 31784484) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jan 29, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G101D variant (also known as c.302G>A), located in coding exon 3 of the MLH1 gene, results from a G to A substitution at nucleotide position 302. The glycine at codon 101 is replaced by aspartic acid, an amino acid with similar properties. Two in vitro functional studies demonstrated reduced MMR function for p.G101D when compared to wild-type MLH1 in yeast (Ellison AR et al. Nucleic Acids Res. 2004 ; 32(18):5321-38; Hinrichsen I et al. Clin. Cancer Res. 2013 May; 19(9):2432-41). The Hinrichsen study also found decreased expression (10-20% relative expression) for this variant when compared to wild-type. Based on internal structural analysis, this variant is highly destabilizing and resides in a known motif within close proximity to known pathogenic variants (Wu H et al. Acta Crystallogr F Struct Biol Commun. 2015 Aug; 71(Pt 8):981-5; Hol WG et al. Nature. 1978 Jun; 273(5662):443-6). The p.G101D variant was also identified in a family meeting Bethesda guidelines (Taylor CF et al. Hum. Mutat. 2003 Dec; 22(6):428-33). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.17	D
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs267607727; hg19: chr3-37042540; COSMIC: COSV51626599;