NM_001113378.2(FANCI):c.3428C>T (p.Thr1143Ile) AND Fanconi anemia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 12, 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:: RCV000630884.5

Allele description [Variation Report for NM_001113378.2(FANCI):c.3428C>T (p.Thr1143Ile)]

NM_001113378.2(FANCI):c.3428C>T (p.Thr1143Ile)

Gene:

FANCI:FA complementation group I [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q26.1

Genomic location:

Preferred name:

NM_001113378.2(FANCI):c.3428C>T (p.Thr1143Ile)

HGVS:

NC_000015.10:g.89306085C>T
NG_008218.2:g.33711G>A
NG_011736.1:g.67123C>T
NM_001113378.2:c.3428C>TMANE SELECT
NM_001376910.1:c.3149C>T
NM_001376911.1:c.3428C>T
NM_018193.3:c.3248C>T
NP_001106849.1:p.Thr1143Ile
NP_001106849.1:p.Thr1143Ile
NP_001363839.1:p.Thr1050Ile
NP_001363840.1:p.Thr1143Ile
NP_060663.2:p.Thr1083Ile
LRG_500t1:c.3428C>T
LRG_500:g.67123C>T
LRG_500p1:p.Thr1143Ile
LRG_765:g.33711G>A
NC_000015.9:g.89849316C>T
NM_001113378.1:c.3428C>T

Protein change:

T1050I

Links:

dbSNP: rs772071601

NCBI 1000 Genomes Browser:

rs772071601

Molecular consequence:

NM_001113378.2:c.3428C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001376910.1:c.3149C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001376911.1:c.3428C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_018193.3:c.3248C>T - 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
SCV000751857	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 12, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28678401, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000751857

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 12, 2022)

germline

clinical testing

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

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

Assessing the spectrum of germline variation in Fanconi anemia genes among patients with head and neck carcinoma before age 50.

Chandrasekharappa SC, Chinn SB, Donovan FX, Chowdhury NI, Kamat A, Adeyemo AA, Thomas JW, Vemulapalli M, Hussey CS, Reid HH, Mullikin JC, Wei Q, Sturgis EM.

Cancer. 2017 Oct 15;123(20):3943-3954. doi: 10.1002/cncr.30802. Epub 2017 Jul 5.

PubMed [citation]

PMID:: 28678401
PMCID:: PMC5853120

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000751857.3

#	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 threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1143 of the FANCI protein (p.Thr1143Ile). This variant is present in population databases (rs772071601, gnomAD 0.03%). This missense change has been observed in individual(s) with head and neck squamous cell carcinoma (PMID: 28678401). ClinVar contains an entry for this variant (Variation ID: 526363). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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

Last Updated: Feb 7, 2023

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