NM_024675.4:c.18G>T

Variant names:

• chr16-23641140-C-A
• rs587782462
• NM_024675.4:c.18G>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PP3_Moderate PP5_Very_Strong

The NM_024675.4(PALB2):​c.18G>T​(p.Gly6Gly) variant causes a synonymous 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. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000186549: RNA analyses have shown that this alteration creates a cryptic splice donor site resulting in a deletion of part of exon 1, a reading frame shift, and a premature stop codon (p.G6Vfs*26) (Yang C et al. Breast Cancer Res. Treat. 2018 Sep" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G6G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 synonymous
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 0.727
• Publications: 7 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: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000186549: RNA analyses have shown that this alteration creates a cryptic splice donor site resulting in a deletion of part of exon 1, a reading frame shift, and a premature stop codon (p.G6Vfs*26) (Yang C et al. Breast Cancer Res. Treat. 2018 Sep; Ambry internal data).; SCV004358011: "A functional RNA study has shown that this cryptic donor site is used, resulting in a complete disruption of normal splicing in the mutant allele (PMID: 30255452)."; SCV000525381: Exonic variant demonstrated to result in aberrant splicing leading to a predicted null allele in a gene for which loss-of-function is a known mechanism of disease (PMID: 30255452); SCV002774285: Experimental studies indicated this variant disrupted PALB2 mRNA splicing, resulting in a frameshift and premature termination of PALB2 protein synthesis (PMID: 30255452 (2019)).; SCV000633312: Studies have shown that this variant results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 30255452; internal data).; SCV000863527: Experimental study demonstrated that this variant leads to aberrant splicing and deletion of the 3' end of exon 1. It is predicted to lead to a truncated or absent protein (PMID: 30255452).; SCV000919939: "At least one publication reports experimental evidence that this variant affects mRNA splicing leading to a deletion of 32 base pairs in exon 1, which leads to a frameshift and truncated protein (Yang_2019)."
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-23641140-C-A is Pathogenic according to our data. Variant chr16-23641140-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 142432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024675.4. 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.18G>T	p.Gly6Gly	synonymous	Exon 1 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.18G>T	p.Gly6Gly	synonymous	Exon 1 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.18G>T	p.Gly6Gly	synonymous	Exon 1 of 12	NP_001394226.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.18G>T	p.Gly6Gly	synonymous	Exon 1 of 13	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.-851G>T		5_prime_UTR	Exon 1 of 13	ENSP00000454703.2	H3BN63
	PALB2	ENST00000970391.1		c.18G>T	p.Gly6Gly	synonymous	Exon 1 of 12	ENSP00000640450.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 247932 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (7)
5	-	-	Familial cancer of breast (5)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.89
PhyloP100		0.73
PromoterAI		0.50	Over-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: 2
DS_DL_spliceai		0.92		Position offset: -30

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

Other links and lift over

dbSNP: rs587782462; hg19: chr16-23652461;