NM_000136.3(FANCC):c.1561G>A (p.Glu521Lys) AND Fanconi anemia

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 21, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000706885.16

Allele description [Variation Report for NM_000136.3(FANCC):c.1561G>A (p.Glu521Lys)]

NM_000136.3(FANCC):c.1561G>A (p.Glu521Lys)

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.1561G>A (p.Glu521Lys)

HGVS:

NC_000009.12:g.95101823C>T
NG_011707.1:g.220887G>A
NG_027833.2:g.380126C>T
NG_116860.1:g.265C>T
NM_000136.3:c.1561G>AMANE SELECT
NM_001243743.2:c.1561G>A
NP_000127.2:p.Glu521Lys
NP_000127.2:p.Glu521Lys
NP_001230672.1:p.Glu521Lys
LRG_497t1:c.1561G>A
LRG_497:g.220887G>A
LRG_497p1:p.Glu521Lys
NC_000009.11:g.97864105C>T
NM_000136.2:c.1561G>A
NM_001243744.1:c.*9373G>A

Protein change:

E521K

Links:

dbSNP: rs752855423

NCBI 1000 Genomes Browser:

rs752855423

Molecular consequence:

NM_000136.3:c.1561G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001243743.2:c.1561G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Fanconi anemia (FA)
Synonyms:: Fanconi pancytopenia; Fanconi's anemia
Identifiers:: MONDO: MONDO:0019391; MeSH: D005199; MedGen: C0015625; Orphanet: 84; OMIM: PS227650

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000835959	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 21, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30613976, 28492532
SCV002081134	Natera, Inc.	no assertion criteria provided	Uncertain significance (Aug 12, 2018)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000835959

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 21, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002081134

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Aug 12, 2018)

germline

clinical testing

Help

Summary from all submissions

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

Citations

PubMed

Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy.

Rizzolo P, Zelli V, Silvestri V, Valentini V, Zanna I, Bianchi S, Masala G, Spinelli AM, Tibiletti MG, Russo A, Varesco L, Giannini G, Capalbo C, Calistri D, Cortesi L, Viel A, Bonanni B, Azzollini J, Manoukian S, Montagna M, Peterlongo P, Radice P, et al.

Int J Cancer. 2019 Jul 15;145(2):390-400. doi: 10.1002/ijc.32106. Epub 2019 Jan 24. Erratum in: Int J Cancer. 2020 Jul 15;147(2):E2. doi: 10.1002/ijc.32944.

PubMed [citation]

PMID:: 30613976

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000835959.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 521 of the FANCC protein (p.Glu521Lys). This variant is present in population databases (rs752855423, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer (PMID: 30613976). ClinVar contains an entry for this variant (Variation ID: 234512). 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: "Probably 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.

#	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

From Natera, Inc., SCV002081134.1

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

#	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: Sep 29, 2024

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