VCV000407899.25 - ClinVar

NM_032444.4(SLX4):c.2305G>C (p.Glu769Gln)

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.

(12)

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_032444.4(SLX4):c.2305G>C (p.Glu769Gln)

Variation ID: 407899 Accession: VCV000407899.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p13.3 16: 3592721 (GRCh38) [ NCBI UCSC ] 16: 3642722 (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	Oct 10, 2018	Oct 8, 2024	Oct 31, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_032444.4:c.2305G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_115820.2:p.Glu769Gln	missense
NC_000016.10:g.3592721C>G
NC_000016.9:g.3642722C>G
NG_028123.1:g.23864G>C
LRG_503:g.23864G>C
LRG_503t1:c.2305G>C

... more HGVS ... less HGVS

Protein change

E769Q

Other names

Canonical SPDI

NC_000016.10:3592720:C:G

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.

0.00040 (G)

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

1000 Genomes Project 30x 0.00031

1000 Genomes Project 0.00040

Exome Aggregation Consortium (ExAC) 0.00098

The Genome Aggregation Database (gnomAD), exomes 0.00100

The Genome Aggregation Database (gnomAD) 0.00119

Trans-Omics for Precision Medicine (TOPMed) 0.00130

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00146

Links

dbSNP: rs150712805 ClinGen: CA7866204 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.
SLX4		-	-	GRCh38 GRCh37	2175	2237

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.
Fanconi anemia	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Oct 31, 2022	RCV000463301.12
Fanconi anemia complementation group P	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	May 4, 2022	RCV001121834.10
not specified	Uncertain significance (1)	criteria provided, single submitter	Nov 22, 2021	RCV001821253.4
not provided	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Mar 3, 2022	RCV001796060.7
SLX4-related disorder	Likely benign (1)	no assertion criteria provided	Apr 22, 2022	RCV003902645.2

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 (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Fanconi anemia complementation group P Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001280487.1 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 (Dec 04, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group P Affected status: yes Allele origin: unknown	Baylor Genetics Study: CSER-TexasKidsCanSeq Accession: SCV001481518.2 First in ClinVar: Feb 28, 2021 Last updated: Feb 28, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (Nov 22, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002067993.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: This sequence change has been reported in familial breast cancer cases(PMID: 23840564). This sequence change has been described in the gnomAD database with a frequency … (more) This sequence change has been reported in familial breast cancer cases(PMID: 23840564). This sequence change has been described in the gnomAD database with a frequency of 0.16% in the non-Finnish subpopulation (dbSNP rs150712805). The p.Glu769Gln change affects a poorly conserved amino acid residue located in a domain of the SLX4 protein that is known to be functional. The p.Glu769Gln substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Glu769Gln change remains unknown at this time. (less)
Uncertain significance (Sep 03, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Fanconi anemia Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002529297.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The SLX4 c.2305G>C (p.E769Q) variant has been reported in individuals with head and neck carcinoma, breast cancer, and ovarian cancer. However, it was also observed … (more) The SLX4 c.2305G>C (p.E769Q) variant has been reported in individuals with head and neck carcinoma, breast cancer, and ovarian cancer. However, it was also observed in controls (PMID: 28678401, 23840564, 23211700, 32546565, 29641532). It was observed in 211/128374 chromosomes, with one homozygote, in the Non-Finnish European subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 407899). In silico tools suggest the impact of the variant on protein function is neutral 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 (5) PubMed: 28678401‚ 23840564‚ 23211700‚ 32546565‚ 29641532
Uncertain significance (May 04, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group P Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002782458.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Oct 31, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Fanconi anemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000547438.9 First in ClinVar: Apr 17, 2017 Last updated: Feb 07, 2023	Publications: PubMed (4) PubMed: 28492532‚ 23211700‚ 23840564‚ 28678401 Comment: This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 769 of the SLX4 protein … (more) This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 769 of the SLX4 protein (p.Glu769Gln). This variant is present in population databases (rs150712805, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with breast cancer or head and neck carcinoma (PMID: 23211700, 23840564, 28678401). ClinVar contains an entry for this variant (Variation ID: 407899). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 (Mar 03, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002104461.2 First in ClinVar: Mar 19, 2022 Last updated: Mar 04, 2023	Comment: In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer in published literature (Shah 2013); This … (more) In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer in published literature (Shah 2013); This variant is associated with the following publications: (PMID: 19596235, 23840564) (less)
Uncertain significance (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002010301.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Uncertain significance (Oct 14, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group P Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003823914.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002038379.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002033923.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Likely benign (Apr 22, 2022)	no assertion criteria provided Method: clinical testing	SLX4-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004722456.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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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:

This sequence change has been reported in familial breast cancer cases(PMID: 23840564). This sequence change has been described in the gnomAD database with a frequency of 0.16% in the non-Finnish subpopulation (dbSNP rs150712805). The p.Glu769Gln change affects a poorly conserved amino acid residue located in a domain of the SLX4 protein that is known to be functional. The p.Glu769Gln substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Glu769Gln change remains unknown at this time.

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 769 of the SLX4 protein (p.Glu769Gln). This variant is present in population databases (rs150712805, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with breast cancer or head and neck carcinoma (PMID: 23211700, 23840564, 28678401). ClinVar contains an entry for this variant (Variation ID: 407899). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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:

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer in published literature (Shah 2013); This variant is associated with the following publications: (PMID: 19596235, 23840564)

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
Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer.	Song H	Journal of medical genetics	2021	PMID: 32546565
Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers.	Pritchard AL	PloS one	2018	PMID: 29641532
Assessing the spectrum of germline variation in Fanconi anemia genes among patients with head and neck carcinoma before age 50.	Chandrasekharappa SC	Cancer	2017	PMID: 28678401
Assessment of SLX4 Mutations in Hereditary Breast Cancers.	Shah S	PloS one	2013	PMID: 23840564
Low prevalence of SLX4 loss-of-function mutations in non-BRCA1/2 breast and/or ovarian cancer families.	de Garibay GR	European journal of human genetics : EJHG	2013	PMID: 23211700

Text-mined citations for rs150712805 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_032444.4(SLX4):c.2305G>C (p.Glu769Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs150712805 ...