ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.377C>G (p.Thr126Arg)

dbSNP: rs139160837
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000466659 SCV000547759 benign Fanconi anemia 2024-01-25 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000503748 SCV000594645 uncertain significance not specified 2016-10-14 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001118714 SCV001277017 uncertain significance Fanconi anemia complementation group A 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen RCV001172102 SCV001335051 uncertain significance not provided 2020-03-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV001118714 SCV001482550 uncertain significance Fanconi anemia complementation group A 2020-09-11 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4 RCV000466659 SCV002535024 likely benign Fanconi anemia 2020-10-20 criteria provided, single submitter curation
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001172102 SCV004218581 likely benign not provided 2022-12-15 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001172102 SCV001550575 uncertain significance not provided no assertion criteria provided clinical testing The FANCA p.Thr126Arg variant was identified in dbSNP (ID: rs139160837), ClinVar (classified as a VUS by Genetic Services Laboratory, University of Chicago and as likely benign by Invitae for Fanconi Anemia) and Cosmic (FATHMM prediction of neutral; score=0.02) but was not identified in LOVD 3.0. The variant was identified in control databases in 112 of 282582 chromosomes at a frequency of 0.000396 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 72 of 10354 chromosomes (freq: 0.006954), European (non-Finnish) in 38 of 128992 chromosomes (freq: 0.000295) and Other in 2 of 7218 chromosomes (freq: 0.000277); it was not observed in the African, Latino, East Asian, European (Finnish) and South Asian populations. The p.T126R variant was identified in 1/44 cases of familial pancreatic cancer (freq=0.011) but was not identified in 115 controls (Rogers_2004_PMID: 15591268). The variant was also found in 1/417 patients with Fanconi anemia (freq=0.001) along with a BRCA2 mutation (c.8567A>C), however the FANCA p.T126R variant was predicted to be benign (Chandrasekharappa_2017_PMID: 28678401). The variant occurs outside of the splicing consensus sequence however 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan) predict the loss of an unreported 3' splice site. The p.Thr126 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc. RCV000466659 SCV002090772 likely benign Fanconi anemia 2020-01-15 no assertion criteria provided clinical testing

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