VCV000134310.15 - ClinVar

NM_001018115.3(FANCD2):c.983G>A (p.Arg328Gln)

Interpretation:: Benign/Likely benign
Review status:: criteria provided, multiple submitters, no conflicts
Submissions:: 9
First in ClinVar:: Jun 9, 2014
Most recent Submission:: Dec 31, 2022
Last evaluated:: May 5, 2022
Accession:: VCV000134310.15
Variation ID:: 134310
Description:: single nucleotide variant

NM_001018115.3(FANCD2):c.983G>A (p.Arg328Gln)

Allele ID

138049

Variant type

single nucleotide variant

Variant length

1 bp

Cytogenetic location

3p25.3

Genomic location

3: 10043144 (GRCh38) GRCh38 UCSC

3: 10084828 (GRCh37) GRCh37 UCSC

HGVS

Nucleotide	Protein	Molecular consequence
NM_001018115.3:c.983G>A MANE Select	NP_001018125.1:p.Arg328Gln	missense
NM_001319984.2:c.983G>A	NP_001306913.1:p.Arg328Gln	missense
NM_001374253.1:c.983G>A	NP_001361182.1:p.Arg328Gln	missense
NM_001374254.1:c.983G>A	NP_001361183.1:p.Arg328Gln	missense
NM_033084.6:c.983G>A	NP_149075.2:p.Arg328Gln	missense
NC_000003.12:g.10043144G>A
NC_000003.11:g.10084828G>A
NG_007311.1:g.21716G>A
NG_046754.1:g.12298G>A
LRG_306:g.21716G>A
LRG_306t2:c.983G>A
	Q9BXW9:p.Arg328Gln

... more HGVS ... less HGVS

Protein change

R328Q

Other names

Canonical SPDI

NC_000003.12:10043143:G:A

Functional consequence

Global minor allele frequency (GMAF)

0.00599 (A)

Allele frequency

The Genome Aggregation Database (gnomAD) 0.00089

Trans-Omics for Precision Medicine (TOPMed) 0.00250

Exome Aggregation Consortium (ExAC) 0.00395

Trans-Omics for Precision Medicine (TOPMed) 0.00213

The Genome Aggregation Database (gnomAD), exomes 0.00446

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023

The Genome Aggregation Database (gnomAD) 0.00124

1000 Genomes Project 0.00599

Links

ClinGen: CA159423

UniProtKB: Q9BXW9#VAR_025832

dbSNP: rs35625434

VarSome

Aggregate interpretations per condition

Interpreted condition	Interpretation	Number of submissions	Review status	Last evaluated	Variation/condition record
not specified	Benign/Likely benign	4	criteria provided, multiple submitters, no conflicts	Dec 10, 2021	RCV000120984.6
Fanconi anemia	Benign	2	criteria provided, multiple submitters, no conflicts	Dec 17, 2021	RCV001084208.6
Fanconi anemia complementation group D2	Benign/Likely benign	2	criteria provided, multiple submitters, no conflicts	May 5, 2022	RCV001146799.4
not provided	Likely benign	1	criteria provided, single submitter	Oct 3, 2016	RCV000443739.5

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation viewer	Related variants
Gene	OMIM	HI score Help	TS score Help	Variation viewer	Within gene	All
FANCD2		-	-	GRCh38 GRCh37	51	1042
LOC107303338	-	-	-	GRCh38	-	669

Submitted interpretations and evidence

Interpretation (Last evaluated)	Review status (Assertion criteria)	Condition (Inheritance)	Submitter	More information
Benign (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: SCV001307558.1 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Jun 10, 2020)	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: SCV002070976.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Benign (Dec 17, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Fanconi anemia Affected status: unknown Allele origin: germline	Invitae Accession: SCV000291164.7 First in ClinVar: Jul 01, 2016 Last updated: May 16, 2022
Likely benign (May 05, 2022)	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: SCV002799447.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Likely Benign (Oct 03, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics Accession: SCV000511359.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: Converted during submission to Likely benign.
Likely benign (Dec 10, 2021)	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: SCV002051021.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022
Benign (May 06, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Fanconi anemia Affected status: unknown Allele origin: germline	Sema4,Sema4 Accession: SCV002529542.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine,Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001550817.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The FANCD2 p.Arg328Gln variant was identified in 1 of 48 proband chromosomes (frequency: 0.021) from individuals with Fanconi anemia (Nie_2019). The p.R328Q variant was identified … (more) The FANCD2 p.Arg328Gln variant was identified in 1 of 48 proband chromosomes (frequency: 0.021) from individuals with Fanconi anemia (Nie_2019). The p.R328Q variant was identified as a heterozygous variant in a patient with multiple primary malignant neoplasms who also carried multiple variants in other cancer genes, including BRCA2 and MLH3 (Wang_2019_PMID:30942098). The variant was identified in dbSNP (ID: rs35625434) and ClinVar (classified as benign by Invitae and likely benign by Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics) but was not identified in Cosmic. The variant was identified in control databases in 1133 of 268136 chromosomes (11 homozygous) at a frequency of 0.004225 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: Latino in 711 of 35082 chromosomes (freq: 0.02027), South Asian in 243 of 30516 chromosomes (freq: 0.007963), East Asian in 147 of 19252 chromosomes (freq: 0.007636), Other in 22 of 6696 chromosomes (freq: 0.003286), African in 5 of 23600 chromosomes (freq: 0.000212) and European (non-Finnish) in 5 of 118032 chromosomes (freq: 0.000042), but was not observed in the Ashkenazi Jewish, or European (Finnish) populations. The p.Arg328 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. (less)
not provided (Sep 19, 2013)	no assertion provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000085152.1 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

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

The FANCD2 p.Arg328Gln variant was identified in 1 of 48 proband chromosomes (frequency: 0.021) from individuals with Fanconi anemia (Nie_2019). The p.R328Q variant was identified as a heterozygous variant in a patient with multiple primary malignant neoplasms who also carried multiple variants in other cancer genes, including BRCA2 and MLH3 (Wang_2019_PMID:30942098). The variant was identified in dbSNP (ID: rs35625434) and ClinVar (classified as benign by Invitae and likely benign by Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics) but was not identified in Cosmic. The variant was identified in control databases in 1133 of 268136 chromosomes (11 homozygous) at a frequency of 0.004225 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: Latino in 711 of 35082 chromosomes (freq: 0.02027), South Asian in 243 of 30516 chromosomes (freq: 0.007963), East Asian in 147 of 19252 chromosomes (freq: 0.007636), Other in 22 of 6696 chromosomes (freq: 0.003286), African in 5 of 23600 chromosomes (freq: 0.000212) and European (non-Finnish) in 5 of 118032 chromosomes (freq: 0.000042), but was not observed in the Ashkenazi Jewish, or European (Finnish) populations. The p.Arg328 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

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 this variant

Title	Author	Journal	Year	Link
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.	Bodian DL	PloS one	2014	PMID: 24728327

Text-mined citations for rs35625434...

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 Jan 07, 2023

ClinVar Genomic variation as it relates to human health

NM_001018115.3(FANCD2):c.983G>A (p.Arg328Gln)

NM_001018115.3(FANCD2):c.983G>A (p.Arg328Gln)

Aggregate interpretations per condition

Submitted interpretations and evidence

Functional evidence

Citations for this variant

Text-mined citations for rs35625434...