rs138629441

chr9-95247504-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000136.3(FANCC):c.178G>A(p.Val60Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,612,712 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: FANCC NM_000136.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:11
• Conservation: PhyloP100: -0.352

Genes affected

FANCC (HGNC:3584): (FA complementation group C) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group C. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010412216).
• BP6: Variant 9-95247504-C-T is Benign according to our data. Variant chr9-95247504-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127537.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=10, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCC	NM_000136.3	c.178G>A	p.Val60Ile	missense_variant	3/15	ENST00000289081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCC	ENST00000289081.8	c.178G>A	p.Val60Ile	missense_variant	3/15	1	NM_000136.3	P1

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 133 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000885 AC: 222 AN: 250762 Hom.: 0 AF XY: 0.000900 AC XY: 122 AN XY: 135534

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00158 AC: 2309 AN: 1460572 Hom.: 2 Cov.: 30 AF XY: 0.00148 AC XY: 1075 AN XY: 726714

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.0000938

Gnomad4 NFE exome AF: 0.00192

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.000874 AC: 133 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.000646 AC XY: 48 AN XY: 74314

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000786

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00159

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.00135 Hom.: 0

Bravo AF: 0.00113

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000865 AC: 105

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fanconi anemia complementation group C Uncertain:5 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Nov 18, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 14, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 14, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 30, 2023	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. -

not provided Uncertain:2 Benign:3

Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2021	This variant is associated with the following publications: (PMID: 14695169, 23028338, 27621404, 24123366, 15695377) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	FANCC: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 19, 2015	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 25, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 19, 2020	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. -

Fanconi anemia Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 12, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

FANCC-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 15, 2020

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). -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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. -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	0.0050
Dann	Benign	0.33
DEOGEN2	Benign	0.061	T;T;T;.;T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.014	N
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.010	T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.55	N;N;.;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.46	N;N;.;.;N;.;.
REVEL	Benign	0.10
Sift	Benign	0.75	T;T;.;.;T;.;.
Sift4G	Benign	0.72	T;T;T;.;T;.;.
Polyphen		0.0	B;B;.;.;B;.;.
Vest4		0.050
MVP		0.21
MPC		0.046
ClinPred		0.00027	T
GERP RS		-5.4
Varity_R		0.021
gMVP		0.071

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs138629441; hg19: chr9-98009786; COSMIC: COSV104610643;