NM_000249.4(MLH1):c.1517T>C (p.Val506Ala) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Apr 26, 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:: RCV000160534.24

Allele description [Variation Report for NM_000249.4(MLH1):c.1517T>C (p.Val506Ala)]

NM_000249.4(MLH1):c.1517T>C (p.Val506Ala)

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.1517T>C (p.Val506Ala)

Other names:

p.V506A:GTT>GCT

HGVS:

NC_000003.12:g.37028891T>C
NG_007109.2:g.40542T>C
NM_000249.4:c.1517T>CMANE SELECT
NM_001167617.3:c.1223T>C
NM_001167618.3:c.794T>C
NM_001167619.3:c.794T>C
NM_001258271.2:c.1517T>C
NM_001258273.2:c.794T>C
NM_001258274.3:c.794T>C
NM_001354615.2:c.794T>C
NM_001354616.2:c.794T>C
NM_001354617.2:c.794T>C
NM_001354618.2:c.794T>C
NM_001354619.2:c.794T>C
NM_001354620.2:c.1223T>C
NM_001354621.2:c.494T>C
NM_001354622.2:c.494T>C
NM_001354623.2:c.494T>C
NM_001354624.2:c.443T>C
NM_001354625.2:c.443T>C
NM_001354626.2:c.443T>C
NM_001354627.2:c.443T>C
NM_001354628.2:c.1517T>C
NM_001354629.2:c.1418T>C
NM_001354630.2:c.1517T>C
NP_000240.1:p.Val506Ala
NP_000240.1:p.Val506Ala
NP_001161089.1:p.Val408Ala
NP_001161090.1:p.Val265Ala
NP_001161091.1:p.Val265Ala
NP_001245200.1:p.Val506Ala
NP_001245202.1:p.Val265Ala
NP_001245203.1:p.Val265Ala
NP_001341544.1:p.Val265Ala
NP_001341545.1:p.Val265Ala
NP_001341546.1:p.Val265Ala
NP_001341547.1:p.Val265Ala
NP_001341548.1:p.Val265Ala
NP_001341549.1:p.Val408Ala
NP_001341550.1:p.Val165Ala
NP_001341551.1:p.Val165Ala
NP_001341552.1:p.Val165Ala
NP_001341553.1:p.Val148Ala
NP_001341554.1:p.Val148Ala
NP_001341555.1:p.Val148Ala
NP_001341556.1:p.Val148Ala
NP_001341557.1:p.Val506Ala
NP_001341558.1:p.Val473Ala
NP_001341559.1:p.Val506Ala
LRG_216t1:c.1517T>C
LRG_216:g.40542T>C
LRG_216p1:p.Val506Ala
NC_000003.11:g.37070382T>C
NM_000249.3:c.1517T>C
NM_001167617.1:c.1223T>C
P40692:p.Val506Ala
p.V506A

Protein change:

V148A

Links:

UniProtKB: P40692#VAR_004456; dbSNP: rs63749909

NCBI 1000 Genomes Browser:

rs63749909

Molecular consequence:

NM_000249.4:c.1517T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1223T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.794T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.794T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1517T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.794T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.794T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.794T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.794T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.794T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.794T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.794T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1223T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.494T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.494T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.494T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.443T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.443T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.443T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.443T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1517T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1418T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1517T>C - 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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Homo sapiens mRNA for SYMPK protein variant protein
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000212722	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Apr 26, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17510385, 18383312, 19690142, 23403630, 9697702 Citation Link,
SCV000911974	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 11, 2023)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 8574961, 9697702, 10037723, 12810663, 17510385, 18383312, 19250818, 22426235, 23403630, 25980754, 31391288, 36054288, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000212722

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Apr 26, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV000911974

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 11, 2023)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

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

Comprehensive molecular analysis of mismatch repair gene defects in suspected Lynch syndrome (hereditary nonpolyposis colorectal cancer) cases.

Mueller J, Gazzoli I, Bandipalliam P, Garber JE, Syngal S, Kolodner RD.

Cancer Res. 2009 Sep 1;69(17):7053-61. doi: 10.1158/0008-5472.CAN-09-0358. Epub 2009 Aug 18.

PubMed [citation]

PMID:: 19690142
PMCID:: PMC2761236

Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients.

Liu B, Parsons R, Papadopoulos N, Nicolaides NC, Lynch HT, Watson P, Jass JR, Dunlop M, Wyllie A, Peltomäki P, de la Chapelle A, Hamilton SR, Vogelstein B, Kinzler KW.

Nat Med. 1996 Feb;2(2):169-74.

PubMed [citation]

PMID:: 8574961

See all PubMed Citations (14)

Details of each submission

From Ambry Genetics, SCV000212722.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.V506A variant (also known as c.1517T>C), located in coding exon 13 of the MLH1 gene, results from a T to C substitution at nucleotide position 1517. The valine at codon 506 is replaced by alanine, an amino acid with similar properties. This alteration was identified in several individuals whose family history met Amsterdam I/II criteria for Lynch syndrome and/or tumors showed loss of MLH1 and/or PMS2 protein expression on immunohistochemistry (IHC) as well as high microsatellite instability (MSI-H) (Ambry internal data; Liu B et al. Nat. Med. 1996 Feb;2:169-74; ). This alteration has also been observed in an individual whose colorectal tumor demonstrated normal mismatch repair protein expression on IHC (Ambry internal data). Multiple yeast-based functional studies of this variant have demonstrated reduced binding of the V506A hMLH1 protein with hPMS2 when compared to wild-type hMLH1 (Guerrette S et al. J. Biol. Chem. 1999 Mar 5;274:6336-41; Kondo E et al. Cancer Res. 2003 Jun;63:3302-8; Shimodaira H et al. Nat. Genet. 1998 Aug;19:384-9). Further, multiple functional studies where cell lines were transfected with this alteration have been shown to exhibit reduced MLH1 expression; however, in vitro functional assays showed that mismatch repair activity was comparable to wild-type (Hinrichsen I et al. Clin. Cancer Res. 2013 May;19:2432-41; Takahashi M et al. Cancer Res. 2007 May;67:4595-604). This amino acid position is well 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.

#	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, SCV000911974.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This missense variant replaces valine with alanine at codon 506 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant reduced MLH1 protein expression (PMID: 9697702, 17510385, 23403630), disrupted PMS2 and EXO1 binding activity (PMID: 10037723, 12810663), and reduced dominant mutator effect (PMID: 9697702, 17510385). However, the impact of this variant on DNA mismatch repair activity remains unclear (PMID: 17510385, 23403630, 36054288). This variant has been reported in individuals and families affected with Lynch Syndrome (PMID: 8574961, 18383312, 19250818, 22426235, 25980754, 31391288). This variant has been identified in 1/31390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	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: Nov 3, 2024

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