rs876659859

chr16-23607864-C-Gchr16-23607864-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_024675.4(PALB2):c.3350G>C(p.Arg1117Thr) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1117K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PALB2 NM_024675.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.18

Genes affected

PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-23607864-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 232594.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.3350G>C	p.Arg1117Thr	missense_variant, splice_region_variant	12/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.3350G>C	p.Arg1117Thr	missense_variant, splice_region_variant	12/13	1	NM_024675.4	P1
	ENST00000561764.1	n.185+481C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	0.0060	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	25
Dann	Benign	0.96
DEOGEN2	Benign	0.12	T;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.3	D;D
Sift	Uncertain	0.0090	D;D
Sift4G	Benign	0.15	T;T
Polyphen		1.0	.;D
Vest4		0.82
MutPred		0.46		.;Gain of catalytic residue at F1118 (P = 0.1213);
MVP		0.66
MPC		0.11
ClinPred		0.96	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-23619185;