VCV000134313.40 - ClinVar

NM_001018115.3(FANCD2):c.1777C>T (p.Pro593Ser)

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.

(14)

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(8); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001018115.3(FANCD2):c.1777C>T (p.Pro593Ser)

Variation ID: 134313 Accession: VCV000134313.40

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p25.3 3: 10062161 (GRCh38) [ NCBI UCSC ] 3: 10103845 (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	Oct 20, 2024	May 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001018115.3:c.1777C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001018125.1:p.Pro593Ser	missense
NM_001319984.2:c.1777C>T	NP_001306913.1:p.Pro593Ser	missense
NM_001374253.1:c.1666C>T	NP_001361182.1:p.Pro556Ser	missense
NM_001374254.1:c.1777C>T	NP_001361183.1:p.Pro593Ser	missense
NM_033084.6:c.1777C>T	NP_149075.2:p.Pro593Ser	missense
NC_000003.12:g.10062161C>T
NC_000003.11:g.10103845C>T
NG_007311.1:g.40733C>T
NG_046754.1:g.31315C>T
LRG_306:g.40733C>T
LRG_306t2:c.1777C>T

... more HGVS ... less HGVS

Protein change

P593S, P556S

Other names

Canonical SPDI

NC_000003.12:10062160: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.

0.00120 (T)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00069

The Genome Aggregation Database (gnomAD) 0.00071

Trans-Omics for Precision Medicine (TOPMed) 0.00080

The Genome Aggregation Database (gnomAD), exomes 0.00088

Exome Aggregation Consortium (ExAC) 0.00098

1000 Genomes Project 0.00120

1000 Genomes Project 30x 0.00125

Links

ClinGen: CA159438 dbSNP: rs147523071 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.
FANCD2		-	-	GRCh38 GRCh37	104	1877
LOC107303338	-	-	-	GRCh38	-	1217

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 29, 2018	RCV000120987.7
Fanconi anemia	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Nov 2, 2022	RCV000459559.13
Fanconi anemia complementation group D2	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Sep 29, 2022	RCV000764454.11
Malignant tumor of breast	Uncertain significance (1)	no assertion criteria provided	Apr 8, 2020	RCV001004843.5
not provided	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	May 1, 2024	RCV001541664.19
FANCD2-related disorder	Uncertain significance (1)	criteria provided, single submitter	Dec 27, 2022	RCV003415914.4

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 (Oct 22, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group D2 Affected status: yes Allele origin: unknown	Baylor Genetics Study: CSER-TexasKidsCanSeq Accession: SCV001481375.2 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 (Dec 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	FANCD2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004115959.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The FANCD2 c.1777C>T variant is predicted to result in the amino acid substitution p.Pro593Ser. This variant has been reported in an individual with unilateral breast … (more) The FANCD2 c.1777C>T variant is predicted to result in the amino acid substitution p.Pro593Ser. This variant has been reported in an individual with unilateral breast cancer (Moradian et al. 2021. PubMed ID: 33558524) and in an individual with head and neck squamous cell carcinoma (Table S3 - Chandrasekharappa et al. 2017. PubMed ID: 28678401). This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is higher than expected for a pathogenic variant (http://gnomad.broadinstitute.org/variant/3-10103845-C-T) and in ClinVar this variant has conflicting interpretations of pathogenicity of uncertain and likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/134313/). 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 (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group D2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000895516.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Fanconi anemia complementation group D2 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001306118.1 First in ClinVar: May 31, 2020 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)
Uncertain significance (Jan 26, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001759689.1 First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021	Comment: In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in an individual with a … (more) In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in an individual with a head and neck squamous cell carcinoma in the literature (Chandrasekharappa et al., 2017); This variant is associated with the following publications: (PMID: 28678401, 24728327, 27626691) (less)
Uncertain significance (Mar 29, 2018)	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: SCV002070980.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Likely benign (Apr 21, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Fanconi anemia Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002529472.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Uncertain significance (Nov 02, 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: SCV000547226.9 First in ClinVar: Apr 17, 2017 Last updated: Feb 07, 2023	Publications: PubMed (2) PubMed: 28492532‚ 33558524 Comment: This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 593 of the FANCD2 protein (p.Pro593Ser). … (more) This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 593 of the FANCD2 protein (p.Pro593Ser). This variant is present in population databases (rs147523071, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 33558524). ClinVar contains an entry for this variant (Variation ID: 134313). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 (Sep 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group D2 Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV000898676.2 First in ClinVar: Apr 25, 2019 Last updated: May 06, 2023	Comment: This variant has not been reported in the literature in association with Fanconi anemia but is present in the Genome Aggregation Database (Highest reported MAF: … (more) This variant has not been reported in the literature in association with Fanconi anemia but is present in the Genome Aggregation Database (Highest reported MAF: 0.1% (184/129068); http://gnomad.broadinstitute.org/variant/3-10103845-C-T). This variant is also present in ClinVar (Variation ID:134313). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
Likely benign (May 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV003916404.13 First in ClinVar: Apr 23, 2023 Last updated: Oct 20, 2024	Comment: FANCD2: BP4, BP5 Number of individuals with the variant: 4
Uncertain significance (Apr 08, 2020)	no assertion criteria provided Method: research	Breast Cancer Affected status: yes Allele origin: germline	Center of Medical Genetics and Primary Health Care Accession: SCV000987266.2 First in ClinVar: Mar 01, 2020 Last updated: Apr 22, 2020	Comment: ACMG Guidelines 2015 criteria BS1 Benign Strong: GnomAD exomes allele frequency = 0.000883 > 0.000584 derived from the 206 clinically reported variants in gene FANCD2 … (more) ACMG Guidelines 2015 criteria BS1 Benign Strong: GnomAD exomes allele frequency = 0.000883 > 0.000584 derived from the 206 clinically reported variants in gene FANCD2 of which 16 PATH, 103 VUS and 87 BEN. BP1 Benign Supporting: 32 out of 35 non-VUS missense variants in gene FANCD2 are BEN = 91.4% > threshold of 51.0%, and 87 out of 206 clinically reported variants in gene FANCD2 are BEN = 42.2% > threshold of 24.0%. BP4 Benign Supporting: 13 benign predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL, SIFT, PolyPhen-2 and Align-GVGD vs no pathogenic predictions and the position is not conserved. 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) Age: 30-39 years Sex: female
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001799087.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
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: SCV001974216.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000085155.1 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
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Comment:

The FANCD2 c.1777C>T variant is predicted to result in the amino acid substitution p.Pro593Ser. This variant has been reported in an individual with unilateral breast cancer (Moradian et al. 2021. PubMed ID: 33558524) and in an individual with head and neck squamous cell carcinoma (Table S3 - Chandrasekharappa et al. 2017. PubMed ID: 28678401). This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is higher than expected for a pathogenic variant (http://gnomad.broadinstitute.org/variant/3-10103845-C-T) and in ClinVar this variant has conflicting interpretations of pathogenicity of uncertain and likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/134313/). 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.

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:

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in an individual with a head and neck squamous cell carcinoma in the literature (Chandrasekharappa et al., 2017); This variant is associated with the following publications: (PMID: 28678401, 24728327, 27626691)

Comment:

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 593 of the FANCD2 protein (p.Pro593Ser). This variant is present in population databases (rs147523071, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 33558524). ClinVar contains an entry for this variant (Variation ID: 134313). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 has not been reported in the literature in association with Fanconi anemia but is present in the Genome Aggregation Database (Highest reported MAF: 0.1% (184/129068); http://gnomad.broadinstitute.org/variant/3-10103845-C-T). This variant is also present in ClinVar (Variation ID:134313). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

Comment:

ACMG Guidelines 2015 criteria BS1 Benign Strong: GnomAD exomes allele frequency = 0.000883 > 0.000584 derived from the 206 clinically reported variants in gene FANCD2 of which 16 PATH, 103 VUS and 87 BEN. BP1 Benign Supporting: 32 out of 35 non-VUS missense variants in gene FANCD2 are BEN = 91.4% > threshold of 51.0%, and 87 out of 206 clinically reported variants in gene FANCD2 are BEN = 42.2% > threshold of 24.0%. BP4 Benign Supporting: 13 benign predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL, SIFT, PolyPhen-2 and Align-GVGD vs no pathogenic predictions and the position is not conserved. 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.

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
Germline mutational spectrum in Armenian breast cancer patients suspected of hereditary breast and ovarian cancer.	Moradian MM	Human genome variation	2021	PMID: 33558524

Text-mined citations for rs147523071 ...

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 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001018115.3(FANCD2):c.1777C>T (p.Pro593Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs147523071 ...