NM_002528.7(NTHL1):c.503T>C (p.Ile168Thr) AND Familial adenomatous polyposis 3

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Oct 28, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV000767388.19

Allele description [Variation Report for NM_002528.7(NTHL1):c.503T>C (p.Ile168Thr)]

NM_002528.7(NTHL1):c.503T>C (p.Ile168Thr)

Gene:

NTHL1:nth like DNA glycosylase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_002528.7(NTHL1):c.503T>C (p.Ile168Thr)

HGVS:

NC_000016.10:g.2044652A>G
NG_005895.1:g.347A>G
NG_008412.1:g.8215T>C
NM_001318193.2:c.355-926T>C
NM_001318194.2:c.173T>C
NM_002528.7:c.503T>CMANE SELECT
NP_001305123.1:p.Ile58Thr
NP_002519.2:p.Ile168Thr
LRG_1366t1:c.503T>C
LRG_1366:g.8215T>C
LRG_1366p1:p.Ile168Thr
LRG_487:g.347A>G
NC_000016.9:g.2094653A>G
NM_002528.5:c.527T>C
NM_002528.6:c.527T>C

Protein change:

I168T

Links:

dbSNP: rs1805378

NCBI 1000 Genomes Browser:

rs1805378

Molecular consequence:

NM_001318193.2:c.355-926T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001318194.2:c.173T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002528.7:c.503T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial adenomatous polyposis 3
Synonyms:: NTHL1-Related Adenomatous Polyposis and Colorectal Cancer; NTHL1-related attenuated familial adenomatous polyposis
Identifiers:: MONDO: MONDO:0014630; MedGen: C4225157; Orphanet: 220460; OMIM: 616415

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000844933	Molecular Oncology Laboratory, Hospital Clínico San Carlos	no assertion criteria provided (ACMG Guidelines, 2015)	Uncertain significance (Jun 1, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001737453	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Likely benign (Oct 28, 2021)	germline	clinical testing	Citation Link,
SCV002049964	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Uncertain significance (Jul 5, 2021)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000844933

Molecular Oncology Laboratory, Hospital Clínico San Carlos

no assertion criteria provided

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 1, 2018)

germline

clinical testing

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

SCV001737453

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

criteria provided, single submitter

(St. Jude Assertion Criteria 2020)

Likely benign
(Oct 28, 2021)

germline

clinical testing

Citation Link,

SCV002049964

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Uncertain significance
(Jul 5, 2021)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Molecular Oncology Laboratory, Hospital Clínico San Carlos, SCV000844933.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV001737453.4

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

Description

The NTHL1 c.527T>C (p.Ile176Thr) missense change has a maximum non-founder subpopulation frequency of 0.3% and a maximum founder subpopulation frequency of 0.54% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/16-2094653-A-G?dataset=gnomad_r2_1). This is higher than expected for a pathogenic variant in NTHL1 (BS1; PMID: 33454955). Seven of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported as heterozygous in individuals with colorectal cancer and adenomatous polyposis (PMID: 31227763, 31285513). It has also been reported as homozygous or compound heterozygous in three individuals with cancer, one of whom has a history of >50 adenomas (PMID: 33454955). This variant has also been reported as homozygous 1x in the gnomAD v2.1.1 database. In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, PP3.

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002049964.1

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

Description

The NTHL1 c.503T>C; p.Ile168Thr variant (rs1805378), also known in alternative nomenclature as p.Ile176Thr, is reported in the literature in multiple heterozygous individuals affected with colorectal cancer or attenuated adenomatous polyposis, although none of these individuals carried a second reported NTHL1 variant (Belhadj 2019, Lorca 2019). This variant is found in the general population with an overall allele frequency of 0.18% (500/277380 alleles, including one homozygote) in the Genome Aggregation Database. The isoleucine at codon 168 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.876). However, due to limited information, the clinical significance of the p.Ile168Thr variant is uncertain at this time. References: Belhadj et al. NTHL1 biallelic mutations seldom cause colorectal cancer, serrated polyposis or a multi-tumor phenotype, in absence of colorectal adenomas. Sci Rep. 2019 Jun 21;9(1):9020. PMID: 31227763. Lorca et al. Contribution of New Adenomatous Polyposis Predisposition Genes in an Unexplained Attenuated Spanish Cohort by Multigene Panel Testing. Sci Rep. 2019 Jul 8;9(1):9814.

#	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: May 19, 2024

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