NM_000249.4:c.1489delC

Variant names:

• chr3-37028857-AC-A
• rs63750855
• NM_000249.4:c.1489delC

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 18 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Very_Strong

The NM_000249.4(MLH1):c.1489delC (p.Arg497GlyfsTer11) variant causes a frameshift change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,844 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000116. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MLH1 NM_000249.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 0.659
• Publications: 1 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: Pathogenic. The variant received 18 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Frameshift (exon 13 of 19) at amino acid 497 of 756, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene. A new stop codon is introduced in the shifted frame, truncating the protein to ~506 amino acids (250 amino acids lost).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000116 — very rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.000636) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s).

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.1489delC p.Arg497GlyfsTer11	frameshift	Exon 13 of 19	Prot: NP_000240.1 UniProt:
	MLH1 NM_001354628.2		c.1489delC p.Arg497GlyfsTer11	frameshift	Exon 13 of 18	Prot: NP_001341557.1 UniProt:
	MLH1 NM_001354629.2		c.1390delC p.Arg464GlyfsTer11	frameshift	Exon 12 of 18	Prot: NP_001341558.1 UniProt:

MLH1 NM_000249.4

MANE Select

HGVSc / HGVSpc.1489delCp.Arg497GlyfsTer11

Exon rankExon 13 of 19

frameshift

Prot: NP_000240.1UniProt: P40692-1

MLH1 NM_001354628.2

HGVSc / HGVSpc.1489delCp.Arg497GlyfsTer11

Exon rankExon 13 of 18

frameshift

Prot: NP_001341557.1UniProt: A0A087WX20

MLH1 NM_001354629.2

HGVSc / HGVSpc.1390delCp.Arg464GlyfsTer11

Exon rankExon 12 of 18

frameshift

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.1489delC p.Arg497GlyfsTer11	frameshift	Exon 13 of 19	Prot: ENSP00000231790.3 UniProt:
	MLH1 ENST00000456676.7	TSL:1	c.1489delC p.Arg497GlyfsTer11	frameshift	Exon 13 of 17	Prot: ENSP00000416687.3 UniProt:
	MLH1 ENST00000413740.2	TSL:1	c.1489delC p.Arg497GlyfsTer11	frameshift	Exon 13 of 15	Prot: ENSP00000416476.2 UniProt:

MLH1 ENST00000231790.8

TSL:1MANE Select

HGVSc / HGVSpc.1489delCp.Arg497GlyfsTer11

Exon rankExon 13 of 19

frameshift

Prot: ENSP00000231790.3UniProt: P40692-1

MLH1 ENST00000456676.7

TSL:1

HGVSc / HGVSpc.1489delCp.Arg497GlyfsTer11

Exon rankExon 13 of 17

frameshift

Prot: ENSP00000416687.3UniProt: H0Y818

MLH1 ENST00000413740.2

TSL:1

HGVSc / HGVSpc.1489delCp.Arg497GlyfsTer11

Exon rankExon 13 of 15

frameshift

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251484	Cov:
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461844	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Colorectal cancer, hereditary nonpolyposis, type 2 (3)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
1	-	-	Lynch syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Benign	0.66

Showing 2 of 2 scores

Splicing Scores

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

Showing 1 of 1 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.

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

dbSNP: rs63750855;

hg19: chr3-37070348;

COSMIC: COSV51614748;

COSMIC: COSV51614748;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar