NM_000249.4(MLH1):c.2210A>T (p.Asp737Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely benign (2 submissions)
Last evaluated:: Mar 23, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000563079.13

Allele description [Variation Report for NM_000249.4(MLH1):c.2210A>T (p.Asp737Val)]

NM_000249.4(MLH1):c.2210A>T (p.Asp737Val)

Gene:

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.2210A>T (p.Asp737Val)

Other names:

p.D737V:GAT>GTT

HGVS:

NC_000003.12:g.37050592A>T
NG_007109.2:g.62243A>T
NM_000249.4:c.2210A>TMANE SELECT
NM_001167617.3:c.1916A>T
NM_001167618.3:c.1487A>T
NM_001167619.3:c.1487A>T
NM_001258271.2:c.2003A>T
NM_001258273.2:c.1487A>T
NM_001258274.3:c.1487A>T
NM_001354615.2:c.1487A>T
NM_001354616.2:c.1487A>T
NM_001354617.2:c.1487A>T
NM_001354618.2:c.1487A>T
NM_001354619.2:c.1487A>T
NM_001354620.2:c.1916A>T
NM_001354621.2:c.1187A>T
NM_001354622.2:c.1187A>T
NM_001354623.2:c.1187A>T
NM_001354624.2:c.1136A>T
NM_001354625.2:c.1136A>T
NM_001354626.2:c.1136A>T
NM_001354627.2:c.1136A>T
NM_001354628.2:c.2117A>T
NM_001354629.2:c.2111A>T
NM_001354630.2:c.2045A>T
NP_000240.1:p.Asp737Val
NP_000240.1:p.Asp737Val
NP_001161089.1:p.Asp639Val
NP_001161090.1:p.Asp496Val
NP_001161091.1:p.Asp496Val
NP_001245200.1:p.Asp668Val
NP_001245202.1:p.Asp496Val
NP_001245203.1:p.Asp496Val
NP_001341544.1:p.Asp496Val
NP_001341545.1:p.Asp496Val
NP_001341546.1:p.Asp496Val
NP_001341547.1:p.Asp496Val
NP_001341548.1:p.Asp496Val
NP_001341549.1:p.Asp639Val
NP_001341550.1:p.Asp396Val
NP_001341551.1:p.Asp396Val
NP_001341552.1:p.Asp396Val
NP_001341553.1:p.Asp379Val
NP_001341554.1:p.Asp379Val
NP_001341555.1:p.Asp379Val
NP_001341556.1:p.Asp379Val
NP_001341557.1:p.Asp706Val
NP_001341558.1:p.Asp704Val
NP_001341559.1:p.Asp682Val
LRG_216t1:c.2210A>T
LRG_216:g.62243A>T
LRG_216p1:p.Asp737Val
NC_000003.11:g.37092083A>T
NM_000249.3:c.2210A>T

Protein change:

D379V

Links:

dbSNP: rs267607885

NCBI 1000 Genomes Browser:

rs267607885

Molecular consequence:

NM_000249.4:c.2210A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1916A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1487A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1487A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.2003A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1487A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1487A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1487A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1487A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1487A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1487A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1487A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1916A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.1187A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.1187A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.1187A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.1136A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.1136A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.1136A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.1136A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.2117A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.2111A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.2045A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000662010	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (May 3, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16341550, 21404117 Citation Link,
SCV000684805	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Mar 23, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000662010

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(May 3, 2018)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000684805

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Mar 23, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Aberrant splicing in MLH1 and MSH2 due to exonic and intronic variants.

Pagenstecher C, Wehner M, Friedl W, Rahner N, Aretz S, Friedrichs N, Sengteller M, Henn W, Buettner R, Propping P, Mangold E.

Hum Genet. 2006 Mar;119(1-2):9-22. Epub 2005 Dec 8.

PubMed [citation]

PMID:: 16341550

Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies.

Hardt K, Heick SB, Betz B, Goecke T, Yazdanparast H, Küppers R, Servan K, Steinke V, Rahner N, Morak M, Holinski-Feder E, Engel C, Möslein G, Schackert HK, von Knebel Doeberitz M, Pox C; Peter Propping.; German HNPCC consortium., Hegemann JH, Royer-Pokora B.

Fam Cancer. 2011 Jun;10(2):273-84. doi: 10.1007/s10689-011-9431-4.

PubMed [citation]

PMID:: 21404117

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000662010.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This alteration is classified as likely 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000684805.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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