VCV000005561.36 - ClinVar

NM_001040108.2(MLH3):c.2221G>T (p.Val741Phe)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(14)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001040108.2(MLH3):c.2221G>T (p.Val741Phe)

Variation ID: 5561 Accession: VCV000005561.36

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q24.3 14: 75047435 (GRCh38) [ NCBI UCSC ] 14: 75514138 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Oct 20, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001040108.2:c.2221G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001035197.1:p.Val741Phe	missense
NM_014381.3:c.2221G>T	NP_055196.2:p.Val741Phe	missense
NC_000014.9:g.75047435C>A
NC_000014.8:g.75514138C>A
NG_008649.1:g.9098G>T
LRG_217:g.9098G>T
LRG_217t1:c.2221G>T	LRG_217p1:p.Val741Phe
	Q9UHC1:p.Val741Phe

... more HGVS ... less HGVS

Protein change

V741F

Other names

Canonical SPDI

NC_000014.9:75047434:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.02596 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.02049

Trans-Omics for Precision Medicine (TOPMed) 0.02075

1000 Genomes Project 0.02596

1000 Genomes Project 30x 0.02608

Links

ClinGen: CA117594 UniProtKB: Q9UHC1#VAR_023347 OMIM: 604395.0007 dbSNP: rs28756990 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
AREL1		-	-	GRCh38 GRCh37	62	79
MLH3		-	-	GRCh38 GRCh37	2587	2616

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Endometrial carcinoma	Pathogenic (1)	no assertion criteria provided	Jul 15, 2007	RCV000005900.3
Colorectal cancer, hereditary nonpolyposis, type 7	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000005901.15
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Dec 1, 2023	RCV000986164.12
not specified	Benign (6)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV001698939.10

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001135069.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Benign (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002551434.4 First in ClinVar: Jul 28, 2022 Last updated: Aug 18, 2023
Benign (Nov 22, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV004562830.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024
Benign (Mar 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848643.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The c.2221G>T (p.Val741Phe) variant in MLH3 is classified as benign since it has ben identified in 5% of African chromosomes in gnomAD, including 35 homozygotes. … (more) The c.2221G>T (p.Val741Phe) variant in MLH3 is classified as benign since it has ben identified in 5% of African chromosomes in gnomAD, including 35 homozygotes. ACMG/AMP Criteria_ BA1. (less)
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005212598.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 7 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000388776.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (3) PubMed: 17656264‚ 12702580‚ 22290698 Comment: 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, … (more) 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 7 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000562032.7 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024
Benign (Jul 30, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002727444.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: 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 … (more) 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. (less)
Benign (Dec 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004699408.8 First in ClinVar: Mar 10, 2024 Last updated: Oct 20, 2024	Comment: MLH3: BP4, BS1, BS2 Number of individuals with the variant: 1
Pathogenic (Jul 15, 2007)	no assertion criteria provided Method: literature only	ENDOMETRIAL CANCER Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026082.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015	Publications: PubMed (2) PubMed: 12702580‚ 17656264 Comment on evidence: In a mother and daughter with endometrial cancer (608089), Liu et al. (2003) identified a heterozygous 2221G-T transversion in exon 1 of the MLH3 gene, … (more) In a mother and daughter with endometrial cancer (608089), Liu et al. (2003) identified a heterozygous 2221G-T transversion in exon 1 of the MLH3 gene, resulting in a val741-to-phe (V741F) substitution. An unaffected aunt, over the age of 80 years, also carried the mutation, indicating reduced penetrance. The mutation was not found in 95 controls. Kim et al. (2007) identified a V741F mutation in a 71-year-old man with colon cancer (HNPCC7; 614385). His 2 sisters developed gastric cancer and breast cancer at ages 57 and 61, respectively. The authors suggested moderate penetrance for this variant. (less)
Pathogenic (Jul 15, 2007)	no assertion criteria provided Method: literature only	COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 7 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026083.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015	Publications: PubMed (2) PubMed: 12702580‚ 17656264 Comment on evidence: In a mother and daughter with endometrial cancer (608089), Liu et al. (2003) identified a heterozygous 2221G-T transversion in exon 1 of the MLH3 gene, … (more) In a mother and daughter with endometrial cancer (608089), Liu et al. (2003) identified a heterozygous 2221G-T transversion in exon 1 of the MLH3 gene, resulting in a val741-to-phe (V741F) substitution. An unaffected aunt, over the age of 80 years, also carried the mutation, indicating reduced penetrance. The mutation was not found in 95 controls. Kim et al. (2007) identified a V741F mutation in a 71-year-old man with colon cancer (HNPCC7; 614385). His 2 sisters developed gastric cancer and breast cancer at ages 57 and 61, respectively. The authors suggested moderate penetrance for this variant. (less)
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002036587.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001919263.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001926422.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021
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Comment:

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Copy number variation analysis detects novel candidate genes involved in follicular growth and oocyte maturation in a cohort of premature ovarian failure cases.	Tšuiko O	Human reproduction (Oxford, England)	2016	PMID: 27301361
Classification of mismatch repair gene missense variants with PON-MMR.	Ali H	Human mutation	2012	PMID: 22290698
MLH3 and EXO1 alterations in familial colorectal cancer patients not fulfilling Amsterdam criteria.	Kim JC	Cancer genetics and cytogenetics	2007	PMID: 17656264
The role of hMLH3 in familial colorectal cancer.	Liu HX	Cancer research	2003	PMID: 12702580

Text-mined citations for rs28756990 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001040108.2(MLH3):c.2221G>T (p.Val741Phe)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28756990 ...