3-36996714-G-C

Variant names:

• chr3-36996714-G-C
• rs587781518
• NM_000249.4:c.207+5G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000249.4(MLH1):​c.207+5G>C variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 NM_000249.4 splice_region, intron
• Scores: Splicing: ADA: 0.9872
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.39
• Publications: 2 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: G2P, ClinGen, Orphanet
• Lynch syndrome 2

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

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

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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 3-36996714-G-C is Pathogenic according to our data. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-36996714-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 141132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.207+5G>C		splice_region_variant, intron_variant	Intron 2 of 18	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.207+5G>C		splice_region_variant, intron_variant	Intron 2 of 18	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Dec 01, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to C nucleotide substitution at the +5 position of intron 2 of the MLH1 gene. A functional RNA study has shown that this variant causes out-of-frame skipping of exon 2, resulting in premature truncation (PMID: 27978560). This variant has been reported in two individuals affected with colorectal cancer that exhibited DNA mismatch repair deficient tumor pathology (PMID: 27978560, 32620519) and to cosegregate with disease in a family with multiple individuals affected with colorectal cancer (PMID: 27978560). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Aug 15, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.207+5G>C intronic variant results from a G to C substitution 5 nucleotides after coding exon 2 in the MLH1 gene. This alteration has been reported in multiple individuals whose family history met Amsterdam criteria for Lynch syndrome and/or had a tumor that demonstrated high microsatellite instability with loss of MLH1 and PMS2 expression by immunohistochemistry (Pearlman R et al. JAMA Oncol. 2017;3(4):464-471; Marabelli M et al. Dig Liver Dis, 2020 Dec;52:1503-1511; Ambry internal data). Analysis of patient-derived RNA found that this alteration results in aberrant splicing leading to transcripts lacking coding exon 2 (Pearlman R et al. JAMA Oncol. 2017;3(4):464-471). In addition, this alteration co-segregates with HNPCC-related tumors in multiple families (Pearlman R et al. JAMA Oncol. 2017;3(4):464-471; Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Lynch syndrome Pathogenic:1

Mar 25, 2016

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;in vitro

RNA evidence indicating exon 2 skipping and familial co-segregation analysis indicated evidence for cosegregation of this variant with colon cancers that have loss of MLH1 on IHC (likelihood ratio 25.28, LOD: 1.4). Taken together this is sufficient evidence for variant pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	0.98
PhyloP100		9.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.87		Position offset: -5

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

Other links and lift over

dbSNP: rs587781518; hg19: chr3-37038205;