Submissions for variant NM_000135.4(FANCA):c.2T>C (p.Met1Thr)

gnomAD frequency: 0.00004  dbSNP: rs769479800

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000669920	SCV000794720	pathogenic	Fanconi anemia complementation group A	2017-10-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000699054	SCV000827749	pathogenic	Fanconi anemia	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the FANCA mRNA. The next in-frame methionine is located at codon 116. This variant is present in population databases (rs769479800, gnomAD 0.01%). Disruption of the initiator codon has been observed in individuals with Fanconi anemia (PMID: 10090479, 15643609, 16084127, 22778927, 23898106, 24584348). ClinVar contains an entry for this variant (Variation ID: 554309). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001509540	SCV001716296	pathogenic	not provided	2020-04-14	criteria provided, single submitter	clinical testing	PVS1_Moderate, PS3, PM2, PM3
Revvity Omics, Revvity	RCV000669920	SCV002022319	pathogenic	Fanconi anemia complementation group A	2021-03-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001509540	SCV002098172	pathogenic	not provided	2022-11-28	criteria provided, single submitter	clinical testing	Identified in patients with Fanconi anemia referred for genetic testing at GeneDx and in published literature (Levran et al., 2005; Li et al., 2018; Mori et al., 2019); Published functional studies demonstrate a damaging effect (Li et al., 2018); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24584348, 10090479, 28060124, 30792206, 23898106, 22778927, 19367192, 16084127, 15643609, 31589614, 30031030)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000669920	SCV003761252	pathogenic	Fanconi anemia complementation group A	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Met1Thr variant in FANCA was identified by our study, in the compound heterozygous state with a likely pathogenic variant (ClinVar Variation ID: 582405) in one individual with Fanconi anemia. Trio exome sequencing analysis revealed that this variant was in trans with another likely pathogenic variant (ClinVar Variation ID: 582405). The p.Met1Thr variant in FANCA has been previously reported in at least six unrelated individuals with Fanconi anemia complementation group A (PMID: 28060124, PMID: 30792206, PMID: 19367192, PMID: 30031030, PMID: 23898106, PMID: 10090479, PMID: 22778927) and segregated with disease in 3 affected members in one family (PMID: 28060124), but has been identified in 0.01% (3/21056) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs769479800). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 554309) and has been interpreted as pathogenic by Counsyl, Mayo Clinic Laboratories, GeneDx, Invitae, the Leiden Open Variant Database, Natera, Inc, and PerkinElmer Genomics. Of these six unrelated individuals who were previously reported (PMID: 28060124, PMID: 30792206, PMID: 19367192, PMID: 30031030, PMID: 23898106, PMID: 10090479, PMID: 22778927), one was a homozygote (PMID: 10090479), and four were compound heterozygotes who carried a pathogenic or likely pathogenic variants in trans (PMID: 28060124, ClinVar Variation ID: 545114; PMID: 30792206; PMID: 19367192; PMID: 23898106, ClinVar Variation ID: 41003) and one was a compound heterozygote who carried a variant of uncertain significance in trans (PMID: 30031030), and, in addition, the variant was found in trans with a pathogenic variant in the individual identified by our study (ClinVar Variation ID: 582405), which increases the likelihood that the p.Met1Thr variant is pathogenic. Five additional pathogenic or likely pathogenic variants, resulting in a different amino acid change at the same position, c.1A>G (p.Met1Val), c.1A>C (p.Met1Leu), c.1A>T (p.Met1Leu), c.2T>A (p.Met1Lys), c.2T>G (p.Met1Arg), and c.3G>T (p.Met1Ile), have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 435134, 553521, 553965, 556239, 934462, 555802). In vitro functional studies provide some evidence that the p.Met1Thr variant may slightly impact protein function (PMID: 30031030). However, these types of assays may not accurately represent biological function. This variant is an initiation codon variant with closest in-frame potential start codon at in exon 4 at Met116 and there are 53 variants classified as pathogenic or likely pathogenic in ClinVar (access date 10/10/2022) upstream of closest in-frame potential start codon (Met116). Loss of function is an established disease mechanism of autosomal recessive Fanconi anemia complementation group A. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Fanconi anemia complementation group A. ACMG/AMP Criteria applied: PVS1_Moderate, PM3_VeryStrong, PS3_Supporting, PM5, PP1 (Richards 2015).
Neuberg Centre For Genomic Medicine, NCGM	RCV000669920	SCV004101504	pathogenic	Fanconi anemia complementation group A		criteria provided, single submitter	clinical testing	The start loss variant c.2T>C (p.Met1?) in FANCA gene has been reported previously in individuals affected with Fanconia anemia (Levran et al., 2005; Gille et al., 2012). In addition, other variants that also affect the initiator methionine of the FANCA mRNA (c.1A>T, c.1A>G, and c.2T>A) have been reported in individuals affected with Fanconi anemia (Chandra et al., 2005). The c.2T>C (p.Met1?) variant is reported with the allele frequency (0.004%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The nucleotide change in FANCA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000699054	SCV004122236	pathogenic	Fanconi anemia	2023-10-27	criteria provided, single submitter	clinical testing	Variant summary: FANCA c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next in-frame methionine is located at codon 116. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 120628 control chromosomes (gnomAD). c.2T>C has been reported in the literature in multiple individuals affected with Fanconi Anemia (examples: Levran_2005, Pinto_2009, Moghrabi_2009, Gille_2012, Li_2018, and Mori_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, in this study this variant was not able to fully rescue MMC sensitivity (Li_2018). The following publications have been ascertained in the context of this evaluation (PMID: 22778927, 15643609, 30031030, 19367192, 30792206, 19278965). Other start loss variants have been classified pathogenic in ClinVar (CV ID 934462, 556239, 554309). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Leiden Open Variation Database	RCV000669920	SCV001425890	pathogenic	Fanconi anemia complementation group A	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Johan de Winter.
Natera, Inc.	RCV000669920	SCV001463137	pathogenic	Fanconi anemia complementation group A	2020-09-16	no assertion criteria provided	clinical testing