NM_000051.4(ATM):c.946T>C (p.Tyr316His) AND not specified

Germline classification:: Uncertain significance (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:: RCV001818502.6

Allele description [Variation Report for NM_000051.4(ATM):c.946T>C (p.Tyr316His)]

NM_000051.4(ATM):c.946T>C (p.Tyr316His)

Gene:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.946T>C (p.Tyr316His)

HGVS:

NC_000011.10:g.108247008T>C
NG_009830.1:g.29177T>C
NM_000051.4:c.946T>CMANE SELECT
NM_001351834.2:c.946T>C
NP_000042.3:p.Tyr316His
NP_000042.3:p.Tyr316His
NP_001338763.1:p.Tyr316His
LRG_135t1:c.946T>C
LRG_135:g.29177T>C
LRG_135p1:p.Tyr316His
NC_000011.9:g.108117735T>C
NM_000051.3:c.946T>C

Protein change:

Y316H

Links:

dbSNP: rs142317485

NCBI 1000 Genomes Browser:

rs142317485

Molecular consequence:

NM_000051.4:c.946T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.946T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002068358	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 14, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003929157	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Apr 26, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28779002, 30613976 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002068358

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 14, 2021)

germline

clinical testing

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

SCV003929157

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Apr 26, 2023)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	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

Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.

Decker B, Allen J, Luccarini C, Pooley KA, Shah M, Bolla MK, Wang Q, Ahmed S, Baynes C, Conroy DM, Brown J, Luben R, Ostrander EA, Pharoah PD, Dunning AM, Easton DF.

J Med Genet. 2017 Nov;54(11):732-741. doi: 10.1136/jmedgenet-2017-104588. Epub 2017 Aug 4.

PubMed [citation]

PMID:: 28779002
PMCID:: PMC5740532

See all PubMed Citations (3)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV002068358.1

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

Description

DNA sequence analysis of the ATM gene demonstrated a sequence change, c.946T>C, in exon 8 that results in an amino acid change, p.Tyr316His. This sequence change has been described in gnomAD with a frequency of 0.011 in the East Asian sub-population. (dbSNP rs142317485). The p.Tyr316His change affects a highly conserved amino acid residue located in a domain of the ATM protein that is known to be functional. The p.Tyr316His substitution appears to be damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in one individual with breast cancer however, it was also identified in two unaffected controls (PMID: 28779002). Due to the lack of sufficient evidences, the clinical significance of the p.Tyr316His change remains unknown at this time.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003929157.1

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

Description

Variant summary: ATM c.946T>C (p.Tyr316His) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250984 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.946T>C has been reported in the literature in an individual affected with breast cancer and in an individual affected with male breast cancer, but has also been reported in control individuals (e.g. Decker_2017, Rizzolo_2019). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30613976, 28779002). Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=8) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as 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

Last Updated: Jan 19, 2025

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