rs28363303

Variant names:

• chr17-58694971-A-C
• rs28363303
• NM_058216.3:c.186A>C

Your query was ambiguous. Multiple possible variants found:

• chr17-58694971-A-C
• chr17-58694971-A-G
• chr17-58694971-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_058216.3(RAD51C):​c.186A>C​(p.Gln62His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. Q62R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: -0.0810
• Publications: 3 publications found

Genes affected

RAD51C (HGNC:9820): (RAD51 paralog C) This gene is a member of the RAD51 family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51 and are known to be involved in the homologous recombination and repair of DNA. This protein can interact with other RAD51 paralogs and is reported to be important for Holliday junction resolution. Mutations in this gene are associated with Fanconi anemia-like syndrome. This gene is one of four localized to a region of chromosome 17q23 where amplification occurs frequently in breast tumors. Overexpression of the four genes during amplification has been observed and suggests a possible role in tumor progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

RAD51C Gene-Disease associations (from GenCC):

• RAD51C-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 3

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Fanconi anemia complementation group O

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3892593).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058216.3. 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
	RAD51C	NM_058216.3	MANE Select	c.186A>C	p.Gln62His	missense	Exon 2 of 9	NP_478123.1	O43502-1
	RAD51C	NM_002876.4		c.186A>C	p.Gln62His	missense	Exon 2 of 2	NP_002867.1	O43502-2
	RAD51C	NR_103872.2		n.228A>C		non_coding_transcript_exon	Exon 2 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	ENST00000337432.9	TSL:1 MANE Select	c.186A>C	p.Gln62His	missense	Exon 2 of 9	ENSP00000336701.4	O43502-1
	RAD51C	ENST00000421782.3	TSL:1	c.186A>C	p.Gln62His	missense	Exon 2 of 2	ENSP00000391450.2	O43502-2
	RAD51C	ENST00000482007.5	TSL:1	n.186A>C		non_coding_transcript_exon	Exon 2 of 8	ENSP00000433332.1	Q7KZJ0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	1	-	Fanconi anemia complementation group O (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	10
DANN	Benign	0.77
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.030
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-0.081
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.19
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.028	D
Polyphen		0.99	D
Vest4		0.32
MutPred		0.39		Loss of catalytic residue at Q62 (P = 0.0331)
MVP		0.72
MPC		0.22
ClinPred		0.96	D
GERP RS		-2.9
PromoterAI		0.018	Neutral
Varity_R		0.20
gMVP		0.49
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28363303; hg19: chr17-56772332;