VCV000319162.26 - ClinVar

NM_032444.4(SLX4):c.2975G>A (p.Gly992Glu)

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.

(9)

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.

Conflicting classifications of pathogenicity
Uncertain significance(7); Benign(1); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_032444.4(SLX4):c.2975G>A (p.Gly992Glu)

Variation ID: 319162 Accession: VCV000319162.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p13.3 16: 3590663 (GRCh38) [ NCBI UCSC ] 16: 3640664 (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	Dec 6, 2016	Feb 20, 2024	Jan 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_032444.4:c.2975G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_115820.2:p.Gly992Glu	missense
NC_000016.10:g.3590663C>T
NC_000016.9:g.3640664C>T
NG_028123.1:g.25922G>A
LRG_503:g.25922G>A
LRG_503t1:c.2975G>A

... more HGVS ... less HGVS

Protein change

G992E

Other names

Canonical SPDI

NC_000016.10:3590662:C:T

Functional
consequence

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

Global minor allele
frequency (GMAF)

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.

0.00060 (T)

Allele frequency

The frequency of the allele represented by this VCV record.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031

Exome Aggregation Consortium (ExAC) 0.00042

1000 Genomes Project 30x 0.00047

The Genome Aggregation Database (gnomAD) 0.00049

The Genome Aggregation Database (gnomAD), exomes 0.00053

1000 Genomes Project 0.00060

Trans-Omics for Precision Medicine (TOPMed) 0.00061

Links

ClinGen: CA7866027

dbSNP: rs139287784

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	2171	2233

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 complementation group P	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Aug 18, 2020	RCV000679857.14
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Mar 17, 2022	RCV002223834.4
not specified	Uncertain significance (1)	criteria provided, single submitter	Jan 19, 2022	RCV001820946.4
SLX4-related disorder	Uncertain significance (1)	criteria provided, single submitter	Jul 11, 2023	RCV003391153.4
Fanconi anemia	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Jan 18, 2024	RCV000351349.16

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 (Jan 13, 2018)	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: SCV000396850.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Likely benign (Aug 18, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group P Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV001984595.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021
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: SCV002010190.3 First in ClinVar: Oct 30, 2021 Last updated: Jul 16, 2023
Uncertain significance (Jan 19, 2022)	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: SCV002067960.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: DNA sequence analysis of the SLX4 gene demonstrated a sequence change, c.2975G>A, in exon 12 which results in an amino acid change, p.Gly992Glu. This sequence … (more) DNA sequence analysis of the SLX4 gene demonstrated a sequence change, c.2975G>A, in exon 12 which results in an amino acid change, p.Gly992Glu. This sequence change does not appear to have been previously described in patients with SLX4-related disorders and has been described in the gnomAD database with a frequency of 0.14% in the Ashkenazi Jewish sub-population (dbSNP rs139287784). The p.Gly992Glu change affects a moderately conserved amino acid residue located in a domain of the SLX4 protein that is not known to be functional. The p.Gly992Glu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to contrasting evidences and the lack of functional studies, the clinical significance of this sequence changes remains unknown at this time. (less)
Uncertain significance (Mar 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502253.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Number of individuals with the variant: 1 Secondary finding: no
Uncertain significance (Nov 29, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Fanconi anemia Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002529316.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The SLX4 c.2975G>A (p.G992E) variant has been reported in heterozygosity in several individuals with leukemia, osteosarcoma, breast, ovarian, and/or lung cancer (PMID: 29891941, 22383991, 23211700, … (more) The SLX4 c.2975G>A (p.G992E) variant has been reported in heterozygosity in several individuals with leukemia, osteosarcoma, breast, ovarian, and/or lung cancer (PMID: 29891941, 22383991, 23211700, 32546565, 30268473, 23840564). It was observed in 142/282556 chromosomes across all populations, with no homozygotes, 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 319162). In silico tools suggest the impact of the variant on protein function is benign, 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 (6) PubMed: 29891941‚ 22383991‚ 23211700‚ 32546565‚ 30268473‚ 23840564
Uncertain significance (Jul 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	SLX4-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004120962.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The SLX4 c.2975G>A variant is predicted to result in the amino acid substitution p.Gly992Glu. This variant has been reported in several large cohorts of patients … (more) The SLX4 c.2975G>A variant is predicted to result in the amino acid substitution p.Gly992Glu. This variant has been reported in several large cohorts of patients with hereditary breast and ovarian cancer (Catucci et al. 2012. PubMed ID: 22383991; De Garibay et al. 2013. PubMed ID: 23211700; Shah et al. 2013. PubMed ID: 23840564; Song et al. 2021. PubMed ID: 32546565) but has also been detected in control populations of ostensibly healthy individuals (Song et al. 2021. PubMed ID: 32546565). Additionally, this variant is reported in 0.14% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-3640664-C-T) and has conflicting interpretations in ClinVar ranging from Uncertain to Benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/319162/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Uncertain significance (Sep 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group P (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV000807207.2 First in ClinVar: Sep 17, 2018 Last updated: Dec 11, 2022	Publications: PubMed (1) PubMed: 25326635 Comment: Possible pathogenicity based on finding it once in our laboratory in trans with another variant in an 8-year-old female with limb reduction defects, mild malar … (more) Possible pathogenicity based on finding it once in our laboratory in trans with another variant in an 8-year-old female with limb reduction defects, mild malar hypoplasia, retrognathia, bluish slerae, mild language delay (less)
Benign (Jan 18, 2024)	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: SCV000547444.9 First in ClinVar: Dec 06, 2016 Last updated: Feb 20, 2024

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

DNA sequence analysis of the SLX4 gene demonstrated a sequence change, c.2975G>A, in exon 12 which results in an amino acid change, p.Gly992Glu. This sequence change does not appear to have been previously described in patients with SLX4-related disorders and has been described in the gnomAD database with a frequency of 0.14% in the Ashkenazi Jewish sub-population (dbSNP rs139287784). The p.Gly992Glu change affects a moderately conserved amino acid residue located in a domain of the SLX4 protein that is not known to be functional. The p.Gly992Glu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to contrasting evidences and the lack of functional studies, the clinical significance of this sequence changes remains unknown at this time.

Comment:

The SLX4 c.2975G>A variant is predicted to result in the amino acid substitution p.Gly992Glu. This variant has been reported in several large cohorts of patients with hereditary breast and ovarian cancer (Catucci et al. 2012. PubMed ID: 22383991; De Garibay et al. 2013. PubMed ID: 23211700; Shah et al. 2013. PubMed ID: 23840564; Song et al. 2021. PubMed ID: 32546565) but has also been detected in control populations of ostensibly healthy individuals (Song et al. 2021. PubMed ID: 32546565). Additionally, this variant is reported in 0.14% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-3640664-C-T) and has conflicting interpretations in ClinVar ranging from Uncertain to Benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/319162/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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
Probable hereditary familial overlap syndrome with multiple synchronous lung tumors.	Cardona AF	Lung cancer (Amsterdam, Netherlands)	2018	PMID: 30268473
Rare variants in Fanconi anemia genes are enriched in acute myeloid leukemia.	Maung KZY	Blood cancer journal	2018	PMID: 29891941
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
Sequencing analysis of SLX4/FANCP gene in Italian familial breast cancer cases.	Catucci I	PloS one	2012	PMID: 22383991

Text-mined citations for rs139287784 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_032444.4(SLX4):c.2975G>A (p.Gly992Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs139287784 ...