VCV000133636.32 - ClinVar

NM_000051.4(ATM):c.8071C>T (p.Arg2691Cys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(15)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000051.4(ATM):c.8071C>T (p.Arg2691Cys)

Variation ID: 133636 Accession: VCV000133636.32

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q22.3 11: 108335029 (GRCh38) [ NCBI UCSC ] 11: 108205756 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 9, 2014	Jun 17, 2024	Feb 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000051.4:c.8071C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000042.3:p.Arg2691Cys	missense
NM_001330368.2:c.641-25958G>A		intron variant
NM_001351110.2:c.*38+191G>A		intron variant
NM_001351834.2:c.8071C>T	NP_001338763.1:p.Arg2691Cys	missense
NC_000011.10:g.108335029C>T
NC_000011.9:g.108205756C>T
NG_009830.1:g.117198C>T
NG_054724.1:g.139804G>A
LRG_135:g.117198C>T
LRG_135t1:c.8071C>T	LRG_135p1:p.Arg2691Cys

... more HGVS ... less HGVS

Protein change

R2691C

Other names

Canonical SPDI

NC_000011.10:108335028:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00009

Exome Aggregation Consortium (ExAC) 0.00011

The Genome Aggregation Database (gnomAD) 0.00011

The Genome Aggregation Database (gnomAD), exomes 0.00014

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA157180 dbSNP: rs531980488 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ATM		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	10850	17460
C11orf65	-	-	-	GRCh38 GRCh37	3	6592

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Uncertain significance (2)	criteria provided, single submitter	Mar 17, 2023	RCV000120161.13
Hereditary cancer-predisposing syndrome	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Aug 11, 2023	RCV000131504.23
Ataxia-telangiectasia syndrome	Uncertain significance (5)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000199628.26
not provided	Uncertain significance (1)	criteria provided, single submitter	Dec 8, 2022	RCV000587628.12
Familial cancer of breast	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Feb 9, 2024	RCV001250430.11
Ataxia-telangiectasia syndrome Familial cancer of breast	Uncertain significance (1)	criteria provided, single submitter	Sep 3, 2021	RCV002492419.8
Ovarian cancer	no classifications from unflagged records (1)	no classifications from unflagged records	Oct 11, 2023	RCV003153382.10

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Aug 30, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: no Allele origin: germline	Division of Medical Genetics, University of Washington Study: CSER_CHARM Accession: SCV001424795.1 First in ClinVar: Jul 30, 2020 Last updated: Jul 30, 2020	Comment: The c.8071C>T variant has been reported in individuals with breast cancer [PMID: 12935922, 20305132, 19781682 ] and also in individuals with no history of cancer … (more) The c.8071C>T variant has been reported in individuals with breast cancer [PMID: 12935922, 20305132, 19781682 ] and also in individuals with no history of cancer [PMID: 24728327, 19781682]. The c.8071C>T variant has an allele frequency of 0.0001353 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico tools evaluating evolutionary conservation and impact on protein structure and function suggest that this variant may have a deleterious effect; however, there are no functional studies to verify or refute these predictions. At this time, it is unknown at this time whether or not this variant increases cancer risk; therefore, we interpret it as a variant of uncertain significance. (less) Indication for testing: family history of breast and colorectal cancer
Uncertain significance (Sep 13, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002537834.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The ATM c.8071C>T (p.R2691C) variant has been reported in heterozygosity in individuals with breast cancer, colorectal cancer, non-medullary thyroid cancer, or chronic lymphocytic leukemia as … (more) The ATM c.8071C>T (p.R2691C) variant has been reported in heterozygosity in individuals with breast cancer, colorectal cancer, non-medullary thyroid cancer, or chronic lymphocytic leukemia as well as unaffected controls (PMID: 33471991, 28135145, 28580595, 15756685, 19781682, 20305132, 26530882, 12935922, 21993670). This variant was observed in 12/18374 chromosomes in the East Asian population, including no homozygotes, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 133636). In silico tools suggest the impact of the variant on protein function is deleterious, though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)	Publications: PubMed (9) PubMed: 33471991‚ 28135145‚ 28580595‚ 15756685‚ 19781682‚ 20305132‚ 26530882‚ 12935922‚ 21993670
Uncertain significance (Jul 02, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV000838606.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022
Uncertain significance (Dec 08, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000568336.7 First in ClinVar: Jun 09, 2014 Last updated: Dec 17, 2022	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal history of breast or … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal history of breast or other cancers, but also identified in unaffected controls (Sommer et al., 2003; Heikkinen et al., 2005; Tavtigian et al., 2009; Guarini et al., 2012; Bodian et al., 2014; Yu et al., 2015; Yurgelun et al., 2017; Estiar and Mehdipour, 2018; Hauke et al., 2018; Xie et al., 2018); This variant is associated with the following publications: (PMID: 25563586, 24728327, 30197789, 29731985, 29134647, 12935922, 23633543, 28580595, 26530882, 19781682, 31871109, 15756685, 28135145, 21993670, 29522266, 29880898, 30311369, 33471991, 32107087, 32068069, 28652578, 20305132, 26689913, 31742824, 35406568, 31248605) (less)
Uncertain significance (Mar 17, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000694370.3 First in ClinVar: Mar 17, 2018 Last updated: May 13, 2023	Publications: PubMed (18) PubMed: 24728327‚ 19781682‚ 20305132‚ 12935922‚ 26689913‚ 26530882‚ 21993670‚ 15756685‚ 28135145‚ 28652578‚ 28580595‚ 29522266‚ 31248605‚ 31742824‚ 31871109‚ 32068069‚ 33471991‚ 32107087 Comment: Variant summary: ATM c.8071C>T (p.Arg2691Cys) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. … (more) Variant summary: ATM c.8071C>T (p.Arg2691Cys) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 258358 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00014 vs 0.001), allowing no conclusion about variant significance. c.8071C>T has been reported in the literature in individuals affected with breast cancer, ovarian cancer, chronic lymphocytic leukemia, thyroid cancer, colorectal cancer, prostate cancer and lung cancer (Kwong_2020, Li_2020, Adedokun_2019, Wei_2019, Hauke_2018, Xie_2018, Yurgelun_2017, Lu_2015, Yu_2015, Guarini_2012, Bernstein_2010, Tavtigian_2009, Heikkinen_2005, Sommer_2003). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. One co-occurrence with another pathogenic variant has been reported internally (PALB2 c.1451T>A, p.Leu484X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven ClinVar submitters have assessed the variant since 2014: all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Uncertain significance (Aug 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000682453.5 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 12935922‚ 15756685‚ 19781682‚ 26530882‚ 28135145‚ 31871109‚ 33471991 Comment: This missense variant replaces arginine with cysteine at codon 2691 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on … (more) This missense variant replaces arginine with cysteine at codon 2691 of the ATM 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 12935922, 15756685, 19781682, 31871109, 33471991), colorectal cancer (PMID: 28135145), and thyroid cancer (PMID: 26530882). In a large international case-control study, this variant was reported in 13/60466 breast cancer cases and 9/53461 controls (OR=1.277, 95%CI 0.546 to 2.988, p-value=0.671; PMID: 33471991). In a separate meta-analysis of breast cancer case-control studies, this variant has shown inconclusive association with disease (PMID: 19781682). This variant has also been identified in 34/251216 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. (less)
Uncertain significance (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000254153.10 First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024	Publications: PubMed (9) PubMed: 28492532‚ 12935922‚ 15756685‚ 19781682‚ 20305132‚ 26689913‚ 29522266‚ 31248605‚ 31871109 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2691 of the ATM protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2691 of the ATM protein (p.Arg2691Cys). This variant is present in population databases (rs531980488, gnomAD 0.06%). This missense change has been observed in individual(s) with breast cancer or prostate cancer (PMID: 12935922, 15756685, 19781682, 20305132, 26689913, 29522266, 31248605, 31871109). ClinVar contains an entry for this variant (Variation ID: 133636). 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 disruptive. 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. (less)
Uncertain significance (Feb 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004210111.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Uncertain significance (Jun 01, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000791912.1 First in ClinVar: Aug 04, 2018 Last updated: Aug 04, 2018	Publications: PubMed (1) PubMed: 21993670
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001264108.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: 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, … (more) 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. (less)
Uncertain significance (Sep 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002784428.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Aug 11, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000186493.10 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (8) PubMed: 12935922‚ 15756685‚ 20305132‚ 24728327‚ 26530882‚ 28135145‚ 28580595‚ 31871109 Comment: The p.R2691C variant (also known as c.8071C>T), located in coding exon 54 of the ATM gene, results from a C to T substitution at nucleotide … (more) The p.R2691C variant (also known as c.8071C>T), located in coding exon 54 of the ATM gene, results from a C to T substitution at nucleotide position 8071. The arginine at codon 2691 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals diagnosed with breast cancer (Sommer SS et al. Cancer Genet Cytogenet, 2003 Sep;145:115-20; Heikkinen K et al. Int J Cancer, 2005 Aug;116:69-72; Bernstein JL et al. J Natl Cancer Inst, 2010 Apr;102:475-83; Xie Y et al. Clin Genet, 2018 Jan;93:41-51; Adedokun B et al. Cancer Epidemiol Biomarkers Prev, 2020 02;29:359-367). It has also been reported in an individual with non-medullary thyroid cancer (Yu Y et al. Sci Rep, 2015 Nov;5:16129). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Ataxia-telangiectasia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001462598.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000084303.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic
Likely pathogenic (Jan 01, 2022)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Ovarian cancer Affected status: yes Allele origin: germline	Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University Accession: SCV003843789.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023
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Comment:

The c.8071C>T variant has been reported in individuals with breast cancer [PMID: 12935922, 20305132, 19781682 ] and also in individuals with no history of cancer [PMID: 24728327, 19781682]. The c.8071C>T variant has an allele frequency of 0.0001353 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico tools evaluating evolutionary conservation and impact on protein structure and function suggest that this variant may have a deleterious effect; however, there are no functional studies to verify or refute these predictions. At this time, it is unknown at this time whether or not this variant increases cancer risk; therefore, we interpret it as a variant of uncertain significance.

Comment:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal history of breast or other cancers, but also identified in unaffected controls (Sommer et al., 2003; Heikkinen et al., 2005; Tavtigian et al., 2009; Guarini et al., 2012; Bodian et al., 2014; Yu et al., 2015; Yurgelun et al., 2017; Estiar and Mehdipour, 2018; Hauke et al., 2018; Xie et al., 2018); This variant is associated with the following publications: (PMID: 25563586, 24728327, 30197789, 29731985, 29134647, 12935922, 23633543, 28580595, 26530882, 19781682, 31871109, 15756685, 28135145, 21993670, 29522266, 29880898, 30311369, 33471991, 32107087, 32068069, 28652578, 20305132, 26689913, 31742824, 35406568, 31248605)

Comment:

Variant summary: ATM c.8071C>T (p.Arg2691Cys) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 258358 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00014 vs 0.001), allowing no conclusion about variant significance. c.8071C>T has been reported in the literature in individuals affected with breast cancer, ovarian cancer, chronic lymphocytic leukemia, thyroid cancer, colorectal cancer, prostate cancer and lung cancer (Kwong_2020, Li_2020, Adedokun_2019, Wei_2019, Hauke_2018, Xie_2018, Yurgelun_2017, Lu_2015, Yu_2015, Guarini_2012, Bernstein_2010, Tavtigian_2009, Heikkinen_2005, Sommer_2003). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. One co-occurrence with another pathogenic variant has been reported internally (PALB2 c.1451T>A, p.Leu484X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven ClinVar submitters have assessed the variant since 2014: all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

This missense variant replaces arginine with cysteine at codon 2691 of the ATM 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 12935922, 15756685, 19781682, 31871109, 33471991), colorectal cancer (PMID: 28135145), and thyroid cancer (PMID: 26530882). In a large international case-control study, this variant was reported in 13/60466 breast cancer cases and 9/53461 controls (OR=1.277, 95%CI 0.546 to 2.988, p-value=0.671; PMID: 33471991). In a separate meta-analysis of breast cancer case-control studies, this variant has shown inconclusive association with disease (PMID: 19781682). This variant has also been identified in 34/251216 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.

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2691 of the ATM protein (p.Arg2691Cys). This variant is present in population databases (rs531980488, gnomAD 0.06%). This missense change has been observed in individual(s) with breast cancer or prostate cancer (PMID: 12935922, 15756685, 19781682, 20305132, 26689913, 29522266, 31248605, 31871109). ClinVar contains an entry for this variant (Variation ID: 133636). 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 disruptive. 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.

Comment:

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.

Comment:

The p.R2691C variant (also known as c.8071C>T), located in coding exon 54 of the ATM gene, results from a C to T substitution at nucleotide position 8071. The arginine at codon 2691 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals diagnosed with breast cancer (Sommer SS et al. Cancer Genet Cytogenet, 2003 Sep;145:115-20; Heikkinen K et al. Int J Cancer, 2005 Aug;116:69-72; Bernstein JL et al. J Natl Cancer Inst, 2010 Apr;102:475-83; Xie Y et al. Clin Genet, 2018 Jan;93:41-51; Adedokun B et al. Cancer Epidemiol Biomarkers Prev, 2020 02;29:359-367). It has also been reported in an individual with non-medullary thyroid cancer (Yu Y et al. Sci Rep, 2015 Nov;5:16129). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
Polymorphisms and rare variants identified by next-generation sequencing confer risk for lung cancer in han Chinese population.	Li X	Pathology, research and practice	2020	PMID: 32107087
Germline Mutation in 1338 BRCA-Negative Chinese Hereditary Breast and/or Ovarian Cancer Patients: Clinical Testing with a Multigene Test Panel.	Kwong A	The Journal of molecular diagnostics : JMD	2020	PMID: 32068069
Prevalence of Inherited Mutations in Breast Cancer Predisposition Genes among Women in Uganda and Cameroon.	Adedokun B	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology	2020	PMID: 31871109
Prevalence of hereditary breast and ovarian cancer (HBOC) predisposition gene mutations among 882 HBOC high-risk Chinese individuals.	Shao D	Cancer science	2020	PMID: 31742824
Germline DNA Repair Gene Mutation Landscape in Chinese Prostate Cancer Patients.	Wei Y	European urology	2019	PMID: 31248605
Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer.	Hauke J	Cancer medicine	2018	PMID: 29522266
Mutation screening of 10 cancer susceptibility genes in unselected breast cancer patients.	Xie Y	Clinical genetics	2018	PMID: 28580595
Rare germline variants in ATM are associated with chronic lymphocytic leukemia.	Tiao G	Leukemia	2017	PMID: 28652578
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.	Yurgelun MB	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2017	PMID: 28135145
Patterns and functional implications of rare germline variants across 12 cancer types.	Lu C	Nature communications	2015	PMID: 26689913
Targeted DNA Sequencing Detects Mutations Related to Susceptibility among Familial Non-medullary Thyroid Cancer.	Yu Y	Scientific reports	2015	PMID: 26530882
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.	Bodian DL	PloS one	2014	PMID: 24728327
ATM gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression.	Guarini A	Haematologica	2012	PMID: 21993670
Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study.	Bernstein JL	Journal of the National Cancer Institute	2010	PMID: 20305132
Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer.	Tavtigian SV	American journal of human genetics	2009	PMID: 19781682
Association of common ATM polymorphism with bilateral breast cancer.	Heikkinen K	International journal of cancer	2005	PMID: 15756685
ATM missense mutations are frequent in patients with breast cancer.	Sommer SS	Cancer genetics and cytogenetics	2003	PMID: 12935922
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Text-mined citations for rs531980488 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000051.4(ATM):c.8071C>T (p.Arg2691Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs531980488 ...