chr3-37025749-TT-AC

Variant names:

• chr3-37025749-TT-AC
• NM_000249.4:c.1151_1152delTTinsAC
• MLH1 p.Val384Asp

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_000249.4(MLH1):c.1151_1152delTTinsAC (p.Val384Asp) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.34). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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.V384D: Benign (ClinVar VariationId 41632, 3 stars); 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) The same amino acid change has been reported as oncogenic or likely oncogenic in a clinical somatic variant database. 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: not found (cov: 30)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.34
• Publications: 0 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: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.000636) — PM2 moderate.

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.1151_1152delTTinsAC p.Val384Asp	missense	N/A	Prot: NP_000240.1 UniProt:
	MLH1 NM_001354628.2		c.1151_1152delTTinsAC p.Val384Asp	missense	N/A	Prot: NP_001341557.1 UniProt:
	MLH1 NM_001354629.2		c.1052_1053delTTinsAC p.Val351Asp	missense	N/A	Prot: NP_001341558.1 UniProt:

MLH1 NM_000249.4

MANE Select

HGVSc / HGVSpc.1151_1152delTTinsACp.Val384Asp

Exon rankN/A

missense

Prot: NP_000240.1UniProt: P40692-1

MLH1 NM_001354628.2

HGVSc / HGVSpc.1151_1152delTTinsACp.Val384Asp

Exon rankN/A

missense

Prot: NP_001341557.1UniProt: A0A087WX20

MLH1 NM_001354629.2

HGVSc / HGVSpc.1052_1053delTTinsACp.Val351Asp

Exon rankN/A

missense

Prot: NP_001341558.1UniProt: A0AAQ5BGZ2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MLH1 ENST00000231790.8	TSL:1MANE Select	c.1151_1152delTTinsAC p.Val384Asp	missense	N/A	Prot: ENSP00000231790.3 UniProt:
	MLH1 ENST00000456676.7	TSL:1	c.1151_1152delTTinsAC p.Val384Asp	missense	N/A	Prot: ENSP00000416687.3 UniProt:
	MLH1 ENST00000413740.2	TSL:1	c.1151_1152delTTinsAC p.Val384Asp	missense	N/A	Prot: ENSP00000416476.2 UniProt:

MLH1 ENST00000231790.8

TSL:1MANE Select

HGVSc / HGVSpc.1151_1152delTTinsACp.Val384Asp

Exon rankN/A

missense

Prot: ENSP00000231790.3UniProt: P40692-1

MLH1 ENST00000456676.7

TSL:1

HGVSc / HGVSpc.1151_1152delTTinsACp.Val384Asp

Exon rankN/A

missense

Prot: ENSP00000416687.3UniProt: H0Y818

MLH1 ENST00000413740.2

TSL:1

HGVSc / HGVSpc.1151_1152delTTinsACp.Val384Asp

Exon rankN/A

missense

Prot: ENSP00000416476.2UniProt: 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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:30

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	7.3

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr3-37067240;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar