16-23629194-T-C

Variant names:

• chr16-23629194-T-C
• rs373321719
• NM_024675.4:c.2586+10A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_024675.4(PALB2):​c.2586+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,601,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene PALB2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: PALB2 NM_024675.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: -0.410
• Publications: 3 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]

PALB2 Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• PALB2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Fanconi anemia complementation group N

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• pancreatic cancer, susceptibility to, 3

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for PALB2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 16-23629194-T-C is Benign according to our data. Variant chr16-23629194-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 126661.

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.2586+10A>G		intron	N/A	NP_078951.2
	PALB2	NM_001407296.1		c.2526+10A>G		intron	N/A	NP_001394225.1
	PALB2	NM_001407297.1		c.2514+446A>G		intron	N/A	NP_001394226.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.2586+10A>G		intron	N/A	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.1701+10A>G		intron	N/A	ENSP00000454703.2	H3BN63
	PALB2	ENST00000561514.3	TSL:5	c.2592+10A>G		intron	N/A	ENSP00000460666.3	A0AA52I2C1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000112 AC: 28 AN: 251066 AF XY: 0.000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000237 AC: 344 AN: 1449292 Hom.: 0 Cov.: 31 AF XY: 0.000231 AC XY: 167 AN XY: 721954

African (AFR) AF: 0.0000301 AC: 1 AN: 33190

American (AMR) AF: 0.0000447 AC: 2 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 86032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52874

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5752

European-Non Finnish (NFE) AF: 0.000282 AC: 311 AN: 1101014

Other (OTH) AF: 0.000467 AC: 28 AN: 60016

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74384

African (AFR) AF: 0.0000723 AC: 3 AN: 41466

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.000121

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Familial cancer of breast (3)
-	-	3	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Endometrial carcinoma (1)
-	1	-	Fanconi anemia complementation group N (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.5
DANN	Benign	0.75
PhyloP100		-0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs373321719; hg19: chr16-23640515;