rs1057517585

Variant names:

• chr16-23641155-C-A
• rs1057517585
• ENST00000568219.5:c.-866G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-23641155-C-A
• chr16-23641155-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001407304.1(PALB2):​c.-1741G>T variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_001407304.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.95
• Publications: 0 publications found

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]

DCTN5 (HGNC:24594): (dynactin subunit 5) This gene encodes a subunit of dynactin, a component of the cytoplasmic dynein motor machinery involved in minus-end-directed transport. The encoded protein is a component of the pointed-end subcomplex and is thought to bind membranous cargo. A pseudogene of this gene is located on the long arm of chromosome 1. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 16-23641155-C-A is Pathogenic according to our data. Variant chr16-23641155-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2673831.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407304.1. 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
	PALB2	NM_024675.4	MANE Select	c.3G>T	p.Met1?	start_lost	Exon 1 of 13	NP_078951.2
	PALB2	NM_001407304.1		c.-1741G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 13	NP_001394233.1	H3BN63
	PALB2	NM_001407305.1		c.-1017G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	NP_001394234.1	H3BN63

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000568219.5	TSL:1	c.-866G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 13	ENSP00000454703.2	H3BN63
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.3G>T	p.Met1?	start_lost	Exon 1 of 13	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.-866G>T		5_prime_UTR	Exon 1 of 13	ENSP00000454703.2	H3BN63

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.94	T
PhyloP100		3.9
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.29
Sift	Benign	0.040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MutPred		1.0		Gain of catalytic residue at M1 (P = 0.0925)
MVP		0.73
ClinPred		0.99	D
GERP RS		5.1
PromoterAI		0.025	Neutral
Varity_R		0.60
gMVP		0.038

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: rs1057517585; hg19: chr16-23652476; COSMIC: COSV99848716; COSMIC: COSV99848716;