ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.77C>T (p.Ser26Phe) (rs1800361)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000120974 SCV000168418 benign not specified 2013-10-24 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120974 SCV000227022 benign not specified 2014-12-29 criteria provided, single submitter clinical testing
Invitae RCV001083879 SCV000262160 benign Fanconi anemia 2020-12-04 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000120974 SCV000296873 benign not specified 2015-10-11 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000120974 SCV000302522 likely benign not specified criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000120974 SCV000594675 likely benign not specified 2015-09-24 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513630 SCV000609344 likely benign not provided 2021-06-01 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000513630 SCV000609628 likely benign not provided 2017-08-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000573438 SCV000673289 likely benign Hereditary cancer-predisposing syndrome 2018-08-31 criteria provided, single submitter clinical testing Other data supporting benign classification;Subpopulation frequency in support of benign classification
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120974 SCV000917335 benign not specified 2018-06-05 criteria provided, single submitter clinical testing Variant summary: FANCC c.77C>T (p.Ser26Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0049 in 276964 control chromosomes in the gnomAD database, including 8 homozygotes. The observed variant frequency is approximately 3-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in FANCC causing Fanconi Anemia Group C phenotype (0.0018), strongly suggesting that the variant is benign. The variant, c.77C>T, was observed in a family, which did not segregate with disease (affected sibling lacking the variant (Verlander_1994).To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.
Mendelics RCV000988227 SCV001137864 likely benign Fanconi anemia, complementation group A 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001168031 SCV001330588 uncertain significance Fanconi anemia, complementation group C 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.
Nilou-Genome Lab RCV001168031 SCV001652743 benign Fanconi anemia, complementation group C 2021-05-18 criteria provided, single submitter clinical testing
ITMI RCV000120974 SCV000085142 not provided not specified 2013-09-19 no assertion provided reference population
Leiden Open Variation Database RCV000513630 SCV001365308 uncertain significance not provided 2020-02-28 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357504 SCV001552990 benign Malignant tumor of breast no assertion criteria provided clinical testing The FANCC p.Ser26Phe variant was identified in 15 of 1470 proband chromosomes (frequency: 0.01) from British and American individuals or families with BRCA1/2 negative breast cancer, pancreatic cancer or leukemias (AML and ALL) and was present in 10 of 2270 control chromosomes (frequency: 0.004) from healthy individuals (Seal 2003, Barber 2003, Couch 2005, Rogers 2004). The variant did not cosegregate with disease in family members with pancreatic cancer, lymphoma or breast cancer in one study (Rogers 2004); was observed 4X greater in sporadic childhood AML patients vs those with ALL in another study (Barber 2003). The variant was also identified in dbSNP (ID: rs1800361) “With other allele”, ClinVar (classified as benign by GeneDx, EGL Genetic Diagnostics(Eurfins Clinical Diagnostics), Invitae, Div. of Genomic Diagnostics (Children's Hospital of Philadelphia); likely benign by Prevention Genetics and classification not provided by ITMI ), Clinvitae (3x), LOVD 3.0 (1x), and was not identified in Cosmic, and MutDB databases. The variant was identified in control databases in 1365 (8 homozygous) of 276964 chromosomes at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 22 (1 homozygous) of 24038 chromosomes (frequency: 0009), Other in 41 of 6462 chromosomes (frequency: 006), Latino in 143 of 34416 chromosomes (frequency: 004), European Non-Finnish in 873 (5 homozygous) of 126482 chromosomes (frequency: 007), Ashkenazi Jewish in 91 of 10144 chromosomes (frequency: 009), European Finnish in 134 (2 homozygous) of 25784 chromosomes (frequency: 005), South Asian in 61 of 30780 chromosomes (frequency: 002), The variant was also identified by our laboratory in 1 individual with breast cancer, co-occurring with a pathogenic BRCA2 mutation (c.8195T>A, p.2732X). The p.Ser26 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Phe variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000120974 SCV001808201 benign not specified no assertion criteria provided clinical testing

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