NM_000136.3(FANCC):c.1604G>A (p.Arg535His) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Apr 4, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000115345.16

Allele description [Variation Report for NM_000136.3(FANCC):c.1604G>A (p.Arg535His)]

NM_000136.3(FANCC):c.1604G>A (p.Arg535His)

Genes:

FANCC:FA complementation group C [Gene - OMIM - HGNC]
AOPEP:aminopeptidase O (putative) [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q22.32

Genomic location:

Preferred name:

NM_000136.3(FANCC):c.1604G>A (p.Arg535His)

Other names:

p.R535H:CGT>CAT

HGVS:

NC_000009.12:g.95101780C>T
NG_011707.1:g.220930G>A
NG_027833.2:g.380083C>T
NG_116860.1:g.222C>T
NM_000136.3:c.1604G>AMANE SELECT
NM_001243743.2:c.1604G>A
NP_000127.2:p.Arg535His
NP_000127.2:p.Arg535His
NP_001230672.1:p.Arg535His
LRG_497t1:c.1604G>A
LRG_497:g.220930G>A
LRG_497p1:p.Arg535His
NC_000009.11:g.97864062C>T
NM_000136.2:c.1604G>A
NM_001243744.1:c.*9416G>A

Protein change:

R535H

Links:

dbSNP: rs587779902

NCBI 1000 Genomes Browser:

rs587779902

Molecular consequence:

NM_000136.3:c.1604G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001243743.2:c.1604G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Mrgprx1 MAS-related GPR, member X1 [Mus musculus]
Mrgprx1 MAS-related GPR, member X1 [Mus musculus]
Gene ID:404242

Gene
404242[uid] AND (alive[prop]) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149254	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Mar 8, 2018)	germline	clinical testing	Citation Link,
SCV003928803	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Apr 4, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000149254

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely benign
(Mar 8, 2018)

germline

clinical testing

Citation Link,

SCV003928803

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Apr 4, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From GeneDx, SCV000149254.14

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003928803.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Variant summary: FANCC c.1604G>A (p.Arg535His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251394 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1604G>A in individuals affected with Fanconi Anemia Group C and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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