3-37040291-T-C

Position:

• chr3-37040291-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000249.4(MLH1):​c.1664T>C​(p.Leu555Pro) variant causes a missense 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 Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L555Q?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.81

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.

• PM1: In a helix (size 14) in uniprot entity MLH1_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_000249.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-37040290-CT-CAAG is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• PP5: Variant 3-37040291-T-C is Pathogenic according to our data. Variant chr3-37040291-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 89822.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040291-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1664T>C	p.Leu555Pro	missense_variant	14/19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1664T>C	p.Leu555Pro	missense_variant	14/19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jul 21, 2023

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 23712482, 30504929, 31784484]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Lynch syndrome Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Jun 21, 2019

Multifactorial likelihood analysis posterior probability 0.95-0.99 -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2019

The p.L555P pathogenic mutation (also known as c.1664T>C), located in coding exon 14 of the MLH1 gene, results from a T to C substitution at nucleotide position 1664. The leucine at codon 555 is replaced by proline, an amino acid with similar properties. This alteration has been identified in individuals that met Amsterdam criteria for Lynch syndrome and their tumors demonstrated loss of both MLH1 and PMS2 on immunohistochemistry (IHC) (Ambry internal data; Farrell MP et al. Fam. Cancer, 2013 Dec;12:741-7). In an in vitro complementation assay, this variant demonstrated mismatch repair (MMR) activity similar to a known pathogenic mutation (Farrell MP et al. Fam. Cancer, 2013 Dec;12:741-7). Another alteration at the same position, p.L555R, has been reported as pathogenic due to its strong segregation with disease in a Lynch syndrome family with several individuals demonstrating high microsatellite instability (MSI-H) or loss of MLH1 and PMS2 on IHC in their tumors (Ambry internal data; Haraldsdottir S et al. Fam. Cancer, 2016 Apr;15:253-60; Roth RM et al. Am. J. Clin. Pathol., 2016 Jul;146:50-6; Haraldsdottir S et al. Genet. Med., 2016 Sep;18:863-8). Based on an internal structural assessment, p.L555P is anticipated to decrease protein stability. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;.;.;.;D
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;.;.;.;D;T
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.4	M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.5	D;D;D;D;D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.99
MutPred		0.80		Gain of disorder (P = 0.014);.;.;.;.;.;.;
MVP		1.0
MPC		0.50
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.99
gMVP		0.95

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: rs587778937; hg19: chr3-37081782;