NM_001048174.2(MUTYH):c.1410G>C (p.Gln470His) AND Familial adenomatous polyposis 2

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Jan 11, 2024
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:: RCV000198891.19

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1410G>C (p.Gln470His)]

NM_001048174.2(MUTYH):c.1410G>C (p.Gln470His)

Gene:

MUTYH:mutY DNA glycosylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p34.1

Genomic location:

Preferred name:

NM_001048174.2(MUTYH):c.1410G>C (p.Gln470His)

HGVS:

NC_000001.11:g.45330540C>G
NG_008189.1:g.14931G>C
NM_001048171.2:c.1410G>C
NM_001048172.2:c.1413G>C
NM_001048173.2:c.1410G>C
NM_001048174.2:c.1410G>CMANE SELECT
NM_001128425.2:c.1494G>C
NM_001293190.2:c.1455G>C
NM_001293191.2:c.1443G>C
NM_001293192.2:c.1134G>C
NM_001293195.2:c.1410G>C
NM_001293196.2:c.1134G>C
NM_001350650.2:c.1065G>C
NM_001350651.2:c.1065G>C
NM_012222.3:c.1485G>C
NP_001041636.1:p.Gln484His
NP_001041636.2:p.Gln470His
NP_001041637.1:p.Gln471His
NP_001041638.1:p.Gln470His
NP_001041639.1:p.Gln470His
NP_001121897.1:p.Gln498His
NP_001121897.1:p.Gln498His
NP_001280119.1:p.Gln485His
NP_001280120.1:p.Gln481His
NP_001280121.1:p.Gln378His
NP_001280124.1:p.Gln470His
NP_001280125.1:p.Gln378His
NP_001337579.1:p.Gln355His
NP_001337580.1:p.Gln355His
NP_036354.1:p.Gln495His
LRG_220t1:c.1494G>C
LRG_220:g.14931G>C
LRG_220p1:p.Gln498His
NC_000001.10:g.45796212C>G
NM_001048171.1:c.1452G>C
NM_001128425.1:c.1494G>C
NR_146882.2:n.1638G>C
NR_146883.2:n.1487G>C
p.Q498H

Protein change:

Q355H

Links:

dbSNP: rs587782794

NCBI 1000 Genomes Browser:

rs587782794

Molecular consequence:

NM_001048171.2:c.1410G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.1413G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.1410G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.1410G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.1494G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.1455G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.1443G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.1134G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.1410G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.1134G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.1065G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.1065G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.1485G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.1638G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.1487G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Familial adenomatous polyposis 2
Synonyms:: COLORECTAL ADENOMATOUS POLYPOSIS, AUTOSOMAL RECESSIVE; ADENOMAS, MULTIPLE COLORECTAL, AUTOSOMAL RECESSIVE; MYH-associated polyposis; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012041; MedGen: C3272841; Orphanet: 220460; OMIM: 608456

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Homo sapiens cDNA clone IMAGE:40122306
Homo sapiens cDNA clone IMAGE:40122306
gi|157742989|gb|BC125185.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000254705	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 11, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16645203, 28492532
SCV000792268	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Jun 13, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16645203, 25525159 Citation Link,
SCV001257604	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 28, 2017)	germline	clinical testing	Citation Link,
SCV004198881	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 27, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004832612	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 15, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16645203, 29684080, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	3	not provided	not provided	108544	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.

Xiong HY, Alipanahi B, Lee LJ, Bretschneider H, Merico D, Yuen RK, Hua Y, Gueroussov S, Najafabadi HS, Hughes TR, Morris Q, Barash Y, Krainer AR, Jojic N, Scherer SW, Blencowe BJ, Frey BJ.

Science. 2015 Jan 9;347(6218):1254806. doi: 10.1126/science.1254806. Epub 2014 Dec 18.

PubMed [citation]

PMID:: 25525159
PMCID:: PMC4362528

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000254705.11

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

Description

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 498 of the MUTYH protein (p.Gln498His). This variant is present in population databases (rs587782794, gnomAD 0.002%). This missense change has been observed in individual(s) with rectal cancer (PMID: 16645203). ClinVar contains an entry for this variant (Variation ID: 142884). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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.

#	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 Counsyl, SCV000792268.1

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

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

From Illumina Laboratory Services, Illumina, SCV001257604.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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 Baylor Genetics, SCV004198881.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004832612.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces glutamine with histidine at codon 498 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with rectal cancer (PMID: 16645203), or thyroid cancer (PMID: 29684080). This variant has been identified in 2/242830 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		3	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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