VCV001787195.4 - ClinVar

NM_000249.4(MLH1):c.2177C>A (p.Ser726Ter)

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.

(3)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000249.4(MLH1):c.2177C>A (p.Ser726Ter)

Variation ID: 1787195 Accession: VCV001787195.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 37050559 (GRCh38) [ NCBI UCSC ] 3: 37092050 (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	Nov 29, 2022	May 1, 2024	Jul 31, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.2177C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000240.1:p.Ser726Ter	nonsense
NM_001167617.3:c.1883C>A	NP_001161089.1:p.Ser628Ter	nonsense
NM_001167618.3:c.1454C>A	NP_001161090.1:p.Ser485Ter	nonsense
NM_001167619.3:c.1454C>A	NP_001161091.1:p.Ser485Ter	nonsense
NM_001258271.2:c.1970C>A	NP_001245200.1:p.Ser657Ter	nonsense
NM_001258273.2:c.1454C>A	NP_001245202.1:p.Ser485Ter	nonsense
NM_001258274.3:c.1454C>A	NP_001245203.1:p.Ser485Ter	nonsense
NM_001354615.2:c.1454C>A	NP_001341544.1:p.Ser485Ter	nonsense
NM_001354616.2:c.1454C>A	NP_001341545.1:p.Ser485Ter	nonsense
NM_001354617.2:c.1454C>A	NP_001341546.1:p.Ser485Ter	nonsense
NM_001354618.2:c.1454C>A	NP_001341547.1:p.Ser485Ter	nonsense
NM_001354619.2:c.1454C>A	NP_001341548.1:p.Ser485Ter	nonsense
NM_001354620.2:c.1883C>A	NP_001341549.1:p.Ser628Ter	nonsense
NM_001354621.2:c.1154C>A	NP_001341550.1:p.Ser385Ter	nonsense
NM_001354622.2:c.1154C>A	NP_001341551.1:p.Ser385Ter	nonsense
NM_001354623.2:c.1154C>A	NP_001341552.1:p.Ser385Ter	nonsense
NM_001354624.2:c.1103C>A	NP_001341553.1:p.Ser368Ter	nonsense
NM_001354625.2:c.1103C>A	NP_001341554.1:p.Ser368Ter	nonsense
NM_001354626.2:c.1103C>A	NP_001341555.1:p.Ser368Ter	nonsense
NM_001354627.2:c.1103C>A	NP_001341556.1:p.Ser368Ter	nonsense
NM_001354628.2:c.2084C>A	NP_001341557.1:p.Ser695Ter	nonsense
NM_001354629.2:c.2078C>A	NP_001341558.1:p.Ser693Ter	nonsense
NM_001354630.2:c.2012C>A	NP_001341559.1:p.Ser671Ter	nonsense
NC_000003.12:g.37050559C>A
NC_000003.11:g.37092050C>A
NG_007109.2:g.62210C>A
LRG_216:g.62210C>A
LRG_216t1:c.2177C>A	LRG_216p1:p.Ser726Ter

... more HGVS ... less HGVS

Protein change

S485*, S657*, S671*, S695*, S726*, S368*, S385*, S628*, S693*

Other names

Canonical SPDI

NC_000003.12:37050558: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.

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

Links

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.
MLH1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	5691	5752

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.
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Jan 23, 2020	RCV002432828.2
Colorectal cancer, hereditary nonpolyposis, type 2	Pathogenic (1)	criteria provided, single submitter	Jul 25, 2023	RCV003454332.1
Hereditary nonpolyposis colorectal neoplasms	Pathogenic (1)	criteria provided, single submitter	Jul 31, 2023	RCV003594285.2

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.
Pathogenic (Jul 25, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 2 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004186405.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Pathogenic (Jul 31, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary nonpolyposis colorectal neoplasms Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004310920.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 8797773‚ 18566915‚ 18931482‚ 24802709‚ 27295708 Comment: This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Lys751Serfs3) have been determined to be pathogenic (PMID: 8797773, 18566915, 18931482, 24802709, … (more) This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Lys751Serfs3) have been determined to be pathogenic (PMID: 8797773, 18566915, 18931482, 24802709, 27295708). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1787195). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser726*) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the MLH1 protein. (less)
Pathogenic (Jan 23, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002731446.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The p.S726* pathogenic mutation (also known as c.2177C>A), located in coding exon 19 of the MLH1 gene, results from a C to A substitution at … (more) The p.S726* pathogenic mutation (also known as c.2177C>A), located in coding exon 19 of the MLH1 gene, results from a C to A substitution at nucleotide position 2177. This changes the amino acid from a serine to a stop codon within coding exon 19. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)

Comment:

This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Lys751Serfs*3) have been determined to be pathogenic (PMID: 8797773, 18566915, 18931482, 24802709, 27295708). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1787195). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser726*) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the MLH1 protein.

Comment:

The p.S726* pathogenic mutation (also known as c.2177C>A), located in coding exon 19 of the MLH1 gene, results from a C to A substitution at nucleotide position 2177. This changes the amino acid from a serine to a stop codon within coding exon 19. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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
[Founder mutation in Lynch syndrome].	Cajal AR	Medicina	2016	PMID: 27295708
A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns.	Borelli I	Familial cancer	2014	PMID: 24802709
Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population.	Nilbert M	Familial cancer	2009	PMID: 18566915
Mismatch repair gene mutations in Chinese HNPCC patients.	Sheng JQ	Cytogenetic and genome research	2008	PMID: 18931482
Germline mutations of hMLH1 and hMSH2 genes in Korean hereditary nonpolyposis colorectal cancer.	Han HJ	Journal of the National Cancer Institute	1996	PMID: 8797773

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000249.4(MLH1):c.2177C>A (p.Ser726Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...