Submissions for variant NM_000136.3(FANCC):c.178G>A (p.Val60Ile)

gnomAD frequency: 0.00091  dbSNP: rs138629441

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000224234	SCV000149256	likely benign	not provided	2021-05-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 14695169, 23028338, 27621404, 24123366, 15695377)
Invitae	RCV000197543	SCV000254258	likely benign	Fanconi anemia	2024-01-31	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224234	SCV000281625	likely benign	not provided	2015-08-19	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000224234	SCV000493642	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	FANCC: BP4
Ambry Genetics	RCV000563479	SCV000673290	likely benign	Hereditary cancer-predisposing syndrome	2018-10-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000115347	SCV000917336	likely benign	not specified	2020-11-19	criteria provided, single submitter	clinical testing	Variant summary: FANCC c.178G>A (p.Val60Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00091 in 253266 control chromosomes. This frequency is lower than the estimated maximum frequency expected for a pathogenic variant in FANCC causing Fanconi Anemia Group C (0.00091 vs 0.0018), allowing no conclusion about variant significance. c.178G>A has been reported in the literature in individuals affected with breast, prostate, pancreatic, and head and neck squamous cell carcinoma, as well as in healthy controls (e.g. Seal_2003, Thompson_2012, Chandrasekharappa_2017, Couch_2005, Dudley_2018, Verhagen_2018, Hong_2018, Bonache_2018). These reports suggest that c.178G>A (legacy name 433G>A) is unlikely to be associated with these types of cancer, but do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Group C. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.5585_5588delTGAA, p.V1862fs*11; internal sample). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported, but multiple authors consider the variant as neutral polymorphism (Savoia_1996, Verhagen_2018). Nine other ClinVar submitters (evaluation after 2014) have cited the variant as likely benign (n=5) and uncertain significance (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV003492472	SCV001137858	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000709095	SCV001329923	uncertain significance	Fanconi anemia complementation group C	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Baylor Genetics	RCV000709095	SCV001482698	uncertain significance	Fanconi anemia complementation group C	2020-07-14	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV000709095	SCV001653438	likely benign	Fanconi anemia complementation group C	2021-05-18	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000224234	SCV002010158	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000115347	SCV002068890	uncertain significance	not specified	2019-10-25	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000709095	SCV002495754	uncertain significance	Fanconi anemia complementation group C	2021-11-18	criteria provided, single submitter	clinical testing	FANCC NM_000136.2 exon 3 p.Val60Ile (c.178G>A): This variant has not been reported in the literature in association with Fanconi anemia. This variant is present in 0.2% (108/68,020) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/9-95247504-C-T?dataset=gnomad_r3). This variant is present in ClinVar, with classifications ranging from likely benign to Uncertain significance (Variation ID:127537). This variant amino acid Isoleucine (Ile) is present in more than 30 species including many mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. Splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Sema4, Sema4	RCV000197543	SCV002535101	likely benign	Fanconi anemia	2021-07-12	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000709095	SCV003843136	uncertain significance	Fanconi anemia complementation group C	2023-08-30	criteria provided, single submitter	clinical testing	The FANCC c.178G>A (p.Val60Ile) missense change has a maximum subpopulation frequency of 0.14% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but this prediction has not been confirmed by functional studies. This variant has been reported as heterozygous in two individuals with head and neck squamous cell carcinoma (PMID: 28678401). This variant has not been reported in the literature in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003935098	SCV004754339	likely benign	FANCC-related condition	2020-12-15	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Leiden Open Variation Database	RCV000224234	SCV001365311	uncertain significance	not provided	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
Natera, Inc.	RCV000709095	SCV001463023	uncertain significance	Fanconi anemia complementation group C	2017-11-14	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354572	SCV001549220	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The FANCC p.Val60Ile variant was identified in 4 of 1924 proband chromosomes (frequency: 0.002) from individuals or families with breast or pancreatic cancer and was present in 7 of 2384 control chromosomes (frequency: 0.003) from healthy individuals (Seal 2003, Couch 2005, Thompson 2012). The variant was identified in dbSNP (rs138629441) as “with other allele,” ClinVar (classified as likely benign by GeneDx, Ambry Genetics and 2 other submitters; and uncertain significance by Invitae and 2 other submitters) and LOVD 3.0 (observed 1x). The variant was identified in control databases in 237 of 276,496 chromosomes at a frequency of 0.0009, 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: African in 6 of 23,998 chromosomes (freq: 0.0003), Other in 6 of 6456 chromosomes (freq: 0.001), Latino in 21 of 34,398 chromosomes (freq: 0.0006), European in 181 of 126208 chromosomes (freq: 0.001434), Ashkenazi Jewish in 3 of 10,132 chromosomes (freq: 0.0003), East Asian in 1 of 18,836 chromosomes (freq: 0.00005), Finnish in 4 of 25,692 chromosomes (freq: 0.0002), and South Asian in 15 of 30,776 chromosomes (freq: 0.0005). The p.Val60 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.