rs1800361

Variant names:

• chr9-95249215-G-A
• rs1800361
• NM_000136.3:c.77C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-95249215-G-A
• chr9-95249215-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000136.3(FANCC):​c.77C>T​(p.Ser26Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00579 in 1,614,112 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S26T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0050 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (29 hom.)
• Consequence: FANCC NM_000136.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:21 O:1
• Conservation: PhyloP100: 3.98
• Publications: 35 publications found

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]

FANCC Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• colorectal cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• malignant pancreatic neoplasm

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010334253).
• BP6: Variant 9-95249215-G-A is Benign according to our data. Variant chr9-95249215-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134301.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00587 (8584/1461840) while in subpopulation MID AF = 0.0231 (133/5768). AF 95% confidence interval is 0.0199. There are 29 homozygotes in GnomAdExome4. There are 4198 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCC	NM_000136.3	c.77C>T	p.Ser26Phe	missense_variant	Exon 2 of 15	ENST00000289081.8	NP_000127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCC	ENST00000289081.8	c.77C>T	p.Ser26Phe	missense_variant	Exon 2 of 15	1	NM_000136.3	ENSP00000289081.3

Frequencies

GnomAD3 genomes AF: 0.00502 AC: 764 AN: 152154 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00603

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00713

Gnomad OTH AF: 0.0101

GnomAD2 exomes AF: 0.00486 AC: 1220 AN: 251236 AF XY: 0.00465

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.00894

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00564

Gnomad NFE exome AF: 0.00668

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00587 AC: 8584 AN: 1461840 Hom.: 29 Cov.: 31 AF XY: 0.00577 AC XY: 4198 AN XY: 727228

African (AFR) AF: 0.00167 AC: 56 AN: 33480

American (AMR) AF: 0.00367 AC: 164 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00899 AC: 235 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00185 AC: 160 AN: 86256

European-Finnish (FIN) AF: 0.00509 AC: 272 AN: 53400

Middle Eastern (MID) AF: 0.0231 AC: 133 AN: 5768

European-Non Finnish (NFE) AF: 0.00648 AC: 7205 AN: 1111982

Other (OTH) AF: 0.00594 AC: 359 AN: 60396

GnomAD4 genome AF: 0.00502 AC: 764 AN: 152272 Hom.: 6 Cov.: 32 AF XY: 0.00506 AC XY: 377 AN XY: 74454

African (AFR) AF: 0.000963 AC: 40 AN: 41546

American (AMR) AF: 0.00758 AC: 116 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4818

European-Finnish (FIN) AF: 0.00603 AC: 64 AN: 10606

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00713 AC: 485 AN: 68028

Other (OTH) AF: 0.00995 AC: 21 AN: 2110

Alfa AF: 0.00648 Hom.: 19

Bravo AF: 0.00443

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00465 AC: 565

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00698

EpiControl AF: 0.00842

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:21 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:7 Other:1

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Oct 11, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 29, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 24, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: 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. -

Apr 02, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 05, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: 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. -

not provided Uncertain:1 Benign:4

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 02, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2020

Leiden Open Variation Database

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FANCC: BP4, BS2 -

Fanconi anemia complementation group C Uncertain:1 Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jul 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia Benign:3

Apr 30, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 21, 2018

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FANCC-related disorder Benign:1

Feb 03, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Fanconi anemia complementation group A Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: 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. -

Hereditary cancer-predisposing syndrome Benign:1

Aug 31, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.23
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T;T;.;T;.;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	.;D;D;D;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.010	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.9	M;M;.;.;.;.;.;.
PhyloP100		4.0
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.5	D;D;.;.;D;.;.;.
REVEL	Benign	0.23
Sift	Uncertain	0.0040	D;D;.;.;D;.;.;.
Sift4G	Uncertain	0.010	D;D;D;.;D;.;.;.
Polyphen		1.0	D;D;.;.;D;.;.;.
Vest4		0.26
MVP		0.87
MPC		0.36
ClinPred		0.011	T
GERP RS		4.2
PromoterAI		0.031	Neutral
Varity_R		0.20
gMVP		0.23
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs1800361; hg19: chr9-98011497;