rs63750447

Variant names:

• chr3-37025749-T-A
• rs63750447
• NM_000249.4:c.1151T>A
• MLH1 p.Val384Asp

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -15 classification points (ACMG Germline Pathogenicity v2019). PP3BS1BS2BP6_Very_Strong

The NM_000249.4(MLH1):c.1151T>A (p.Val384Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00101 (AC=1,631) in the gnomAD database across 1,613,706 control chromosomes, including 21 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0332. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.34). Variant has been reported in ClinVar as Benign/Likely Benign (★★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.V384A: Uncertain_significance (ClinVar VariationId 3635648, 1 star); p.V384F: Uncertain_significance (ClinVar VariationId 818423, 2 stars); p.V384I: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 405421); p.V384= (synonymous): Likely_benign (ClinVar VariationId 818432, 2 stars) This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (19 hom.)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Benign reviewed by expert panel B:27 O:1
• Conservation: PhyloP100: 7.34
• Publications: 145 publications found

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]

MLH1 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet
• Lynch syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, Ambry Genetics
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Lynch syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Specifications for MLH1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Benign. The variant received -15 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).
	BP6Reputable source reports benign		ClinVar ≥3 stars benign — very strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 3 star(s). ClinVar submissions strongly and reliably favor benignity (27/27 total B/LB).
	BS1Allele frequency higher than expected		GnomAD effective popmax AF above BS1 threshold — greater than expected for disorder; GnomAD effective popmax AF = 0.0332 vs gene BS1 threshold 0.015.
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 21.; Very high cumulative gnomAD AC = 1631 (any gene).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000249.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	NM_000249.4	MANE Select	c.1151T>A	p.Val384Asp	missense	Exon 12 of 19	NP_000240.1	P40692-1
	MLH1	NM_001354628.2		c.1151T>A	p.Val384Asp	missense	Exon 12 of 18	NP_001341557.1	A0A087WX20
	MLH1	NM_001354629.2		c.1052T>A	p.Val351Asp	missense	Exon 11 of 18	NP_001341558.1	A0AAQ5BGZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	ENST00000231790.8	TSL:1 MANE Select	c.1151T>A	p.Val384Asp	missense	Exon 12 of 19	ENSP00000231790.3	P40692-1
	MLH1	ENST00000456676.7	TSL:1	c.1151T>A	p.Val384Asp	missense	Exon 12 of 17	ENSP00000416687.3	H0Y818
	MLH1	ENST00000413740.2	TSL:1	c.1151T>A	p.Val384Asp	missense	Exon 12 of 15	ENSP00000416476.2	H0Y806

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00105	AC:160	Hom:2	AN:151706	Cov:31
GnomAD2 exomes	AF: 0.00271	AC:682	Hom:	AN:251422	Cov:
GnomAD4 exome	AF: 0.00101	AC:1471	Hom:19	AN:1461884	Cov:34
GnomAD4 genome	AF: 0.00105	AC:160	Hom:2	AN:151822	Cov:31
TOPMed (Bravo)	AF: 0.00142	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000224	AC:6	Hom:0	AN:26752	Cov:
Local & regional cohorts 8 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.0337	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0000769	AC:1	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.00982	AC:34	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.0400	AC:292	Hom:	AN:7230	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0344	AC:4208	Hom:84	AN:122256	Cov:
Turkish Variome	AF: 0.00129	AC:2	Hom:0	AN:1546	Cov:
UK10K	AF: 0.000132	AC:1	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.0300	AC:269	Hom:3	AN:8960	Cov:

Showing 14 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00276	116	41958	0.00126	84	66888
SCHEMA(Schizophrenia)	0.0101	1241	123046	0.00685	1315	191916

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (10)
-	-	4	Colorectal cancer, hereditary nonpolyposis, type 2 (4)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	4	not provided (4)
-	-	1	Bile duct cancer (1)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch syndrome (1)
-	-	1	Lynch syndrome 1 (1)
-	-	1	Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	34
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.97	D
FuncVEP CTI	Pathogenic	0.73
GPN-Star LLR	N/A	-10
GPN-Star score	N/A	10
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.52	D
Mutation Taster	N/A	88/12	polymorphism
MutationAssessor	Uncertain	2.6	M
PhyloP100	Uncertain	7.3
popEVE	Benign	-3.4
PrimateAI	Uncertain	0.58	T
PromoterAI	N/A	0.020	Neutral
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.92
VESM-3B	Benign	-15

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs63750447;

hg19: chr3-37067240;

COSMIC: COSV51614178;

COSMIC: COSV51614178;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar