9-95249289-C-T

Variant names:

• chr9-95249289-C-T
• rs1368374192
• NM_000136.3:c.3G>A
• FANCC p.Met1?

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000136.3(FANCC):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FANCC NM_000136.3 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 5.31
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Myriad Women's Health, ClinGen, G2P
• 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 15 pathogenic variants. Next in-frame start position is after 16 codons. Genomic position: 95249246. Lost 0.027 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-95249289-C-T is Pathogenic according to our data. Variant chr9-95249289-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 632544.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000136.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCC	NM_000136.3	MANE Select	c.3G>A	p.Met1?	start_lost	Exon 2 of 15	NP_000127.2	Q00597
	FANCC	NM_001243743.2		c.3G>A	p.Met1?	start_lost	Exon 2 of 15	NP_001230672.1	A0A024R9N2
	FANCC	NM_001243744.2		c.3G>A	p.Met1?	start_lost	Exon 2 of 14	NP_001230673.1	A0A087WW44

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCC	ENST00000289081.8	TSL:1 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 2 of 15	ENSP00000289081.3	Q00597
	FANCC	ENST00000375305.6	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 2 of 15	ENSP00000364454.1	Q00597
	FANCC	ENST00000490972.7	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 2 of 14	ENSP00000479931.1	A0A087WW44

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Fanconi anemia (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.27	T
PhyloP100		5.3
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
PromoterAI		-0.096	Neutral
Varity_R		0.80
gMVP		0.38
Mutation Taster		=32/168	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1368374192; hg19: chr9-98011571; COSMIC: COSV56668057;