VCV000089915.12 - ClinVar

NM_000249.4(MLH1):c.1877T>C (p.Phe626Ser)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000249.4(MLH1):c.1877T>C (p.Phe626Ser)

Variation ID: 89915 Accession: VCV000089915.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 37047664 (GRCh38) [ NCBI UCSC ] 3: 37089155 (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	Mar 24, 2015	May 1, 2024	Dec 4, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.1877T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000240.1:p.Phe626Ser	missense
NM_001167617.3:c.1583T>C	NP_001161089.1:p.Phe528Ser	missense
NM_001167618.3:c.1154T>C	NP_001161090.1:p.Phe385Ser	missense
NM_001167619.3:c.1154T>C	NP_001161091.1:p.Phe385Ser	missense
NM_001258271.2:c.1877T>C	NP_001245200.1:p.Phe626Ser	missense
NM_001258273.2:c.1154T>C	NP_001245202.1:p.Phe385Ser	missense
NM_001258274.3:c.1154T>C	NP_001245203.1:p.Phe385Ser	missense
NM_001354615.2:c.1154T>C	NP_001341544.1:p.Phe385Ser	missense
NM_001354616.2:c.1154T>C	NP_001341545.1:p.Phe385Ser	missense
NM_001354617.2:c.1154T>C	NP_001341546.1:p.Phe385Ser	missense
NM_001354618.2:c.1154T>C	NP_001341547.1:p.Phe385Ser	missense
NM_001354619.2:c.1154T>C	NP_001341548.1:p.Phe385Ser	missense
NM_001354620.2:c.1583T>C	NP_001341549.1:p.Phe528Ser	missense
NM_001354621.2:c.854T>C	NP_001341550.1:p.Phe285Ser	missense
NM_001354622.2:c.854T>C	NP_001341551.1:p.Phe285Ser	missense
NM_001354623.2:c.854T>C	NP_001341552.1:p.Phe285Ser	missense
NM_001354624.2:c.803T>C	NP_001341553.1:p.Phe268Ser	missense
NM_001354625.2:c.803T>C	NP_001341554.1:p.Phe268Ser	missense
NM_001354626.2:c.803T>C	NP_001341555.1:p.Phe268Ser	missense
NM_001354627.2:c.803T>C	NP_001341556.1:p.Phe268Ser	missense
NM_001354628.2:c.1877T>C	NP_001341557.1:p.Phe626Ser	missense
NM_001354629.2:c.1778T>C	NP_001341558.1:p.Phe593Ser	missense
NM_001354630.2:c.1732-853T>C		intron variant
NC_000003.12:g.37047664T>C
NC_000003.11:g.37089155T>C
NG_007109.2:g.59315T>C
LRG_216:g.59315T>C
LRG_216t1:c.1877T>C	LRG_216p1:p.Phe626Ser

... more HGVS ... less HGVS

Protein change

F626S, F268S, F285S, F385S, F593S, F528S

Other names

Canonical SPDI

NC_000003.12:37047663:T:C

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

ClinGen: CA007302 dbSNP: rs587778952 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 nonpolyposis colorectal neoplasms	Uncertain significance (1)	criteria provided, single submitter	Dec 4, 2023	RCV000696198.6
Hereditary cancer-predisposing syndrome	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	May 20, 2021	RCV001013501.6

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.
Likely pathogenic (May 20, 2021)	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: SCV001174094.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 9048925 Comment: The p.F626S variant (also known as c.1877T>C), located in coding exon 16 of the MLH1 gene, results from a T to C substitution at nucleotide … (more) The p.F626S variant (also known as c.1877T>C), located in coding exon 16 of the MLH1 gene, results from a T to C substitution at nucleotide position 1877. The phenylalanine at codon 626 is replaced by serine, an amino acid with highly dissimilar properties. This alteration is detected in an individual whose colorectal tumor demonstrated loss of MLH1 and PMS2 expression on immunohistochemistry (IHC), and BRAF mutation analysis was negative (Ambry internal data). This alteration was also detected in conjunction with another MLH1 missense alteration (phase unknown) in 1 of 14 families, all of whom meet Amsterdam criteria; however, individual-level clinical data was not provided (Beck NE et al. Hum Genet, 1997 Feb;99:219-24). Based on internal structural analysis using published crystal structures, p.F626S is moderately destabilizing to the local structure (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Uncertain significance (Dec 20, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001339535.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020
Uncertain significance (Dec 04, 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: SCV000824750.5 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 28492532 Comment: This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 626 of the MLH1 protein (p.Phe626Ser). … (more) This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 626 of the MLH1 protein (p.Phe626Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 89915). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)

Comment:

The p.F626S variant (also known as c.1877T>C), located in coding exon 16 of the MLH1 gene, results from a T to C substitution at nucleotide position 1877. The phenylalanine at codon 626 is replaced by serine, an amino acid with highly dissimilar properties. This alteration is detected in an individual whose colorectal tumor demonstrated loss of MLH1 and PMS2 expression on immunohistochemistry (IHC), and BRAF mutation analysis was negative (Ambry internal data). This alteration was also detected in conjunction with another MLH1 missense alteration (phase unknown) in 1 of 14 families, all of whom meet Amsterdam criteria; however, individual-level clinical data was not provided (Beck NE et al. Hum Genet, 1997 Feb;99:219-24). Based on internal structural analysis using published crystal structures, p.F626S is moderately destabilizing to the local structure (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Comment:

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 626 of the MLH1 protein (p.Phe626Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 89915). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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
Use of SSCP analysis to identify germline mutations in HNPCC families fulfilling the Amsterdam criteria.	Beck NE	Human genetics	1997	PMID: 9048925

Text-mined citations for rs587778952 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000249.4(MLH1):c.1877T>C (p.Phe626Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587778952 ...