rs63750449

Positions:

• chr3-37047640-A-C
• chr3-37047640-A-G
• chr3-37047640-A-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 5P and 20B. PM1 PM5 PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000249.4(MLH1):​c.1853A>C​(p.Lys618Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,614,148 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K618A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0039 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0049 (21 hom.)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Benign reviewed by expert panel U:4 B:17 O:1
• Conservation: PhyloP100: 7.33

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 Benign. Variant got -15 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_000249.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-37047640-A-TTCTT is described in ClinVar as [Pathogenic]. Clinvar id is 89908.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.028957754).
• BP6: Variant 3-37047640-A-C is Benign according to our data. Variant chr3-37047640-A-C is described in ClinVar as [Benign]. Clinvar id is 89906.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37047640-A-C is described in Lovd as [Likely_benign]. Variant chr3-37047640-A-C is described in Lovd as [Benign]. Variant chr3-37047640-A-C is described in Lovd as [Pathogenic]. Variant chr3-37047640-A-C is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0039 (594/152306) while in subpopulation AMR AF= 0.00928 (142/15294). AF 95% confidence interval is 0.00804. There are 2 homozygotes in gnomad4. There are 306 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4	c.1853A>C	p.Lys618Thr	missense_variant	16/19	ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8	c.1853A>C	p.Lys618Thr	missense_variant	16/19	1	NM_000249.4	P1

Frequencies

GnomAD3 genomes AF: 0.00391 AC: 595 AN: 152188 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00930

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00553

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00347 AC: 873 AN: 251414 Hom.: 4 AF XY: 0.00342 AC XY: 465 AN XY: 135870

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00445

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00572

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00487 AC: 7113 AN: 1461842 Hom.: 21 Cov.: 31 AF XY: 0.00470 AC XY: 3417 AN XY: 727230

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.00467

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000786

Gnomad4 NFE exome AF: 0.00591

Gnomad4 OTH exome AF: 0.00402

GnomAD4 genome AF: 0.00390 AC: 594 AN: 152306 Hom.: 2 Cov.: 31 AF XY: 0.00411 AC XY: 306 AN XY: 74472

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00928

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00551

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00149 Hom.: 0

Bravo AF: 0.00400

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00341 AC: 414

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00600

EpiControl AF: 0.00581

ClinVar

Significance: Benign

Submissions summary: Uncertain:4 Benign:17 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1 Benign:6

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 12, 2019	- -
Uncertain significance, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 10, 2020	The p.Lys618Thr variant in MLH1 is classified as benign because it has been identified in 0.57% (735/129116, 2 homozygotes) chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is a common haplotype with c.1852A>G. ACMG/AMP Criteria applied: BA1. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 24, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 03, 2017	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 01, 2022	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Nov 22, 2022	- -

not provided Uncertain:1 Benign:1 Other:1

not provided, no classification provided	literature only	Harris Lab, University of Minnesota	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	MLH1: PP3, BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 10, 2019	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Colorectal cancer, non-polyposis Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 22, 2023

- -

Lynch syndrome 1 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Pathway Genomics

Jul 24, 2014

- -

Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 21, 2022

- -

Lynch syndrome Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Multifactorial likelihood analysis posterior probability <0.001 -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;.;.;.;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.029	T;T;T;T;T;T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.4	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0020	D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.91
MVP		0.97
MPC		0.41
ClinPred		0.074	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.83

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: rs63750449; hg19: chr3-37089131; COSMIC: COSV51620718;