16-23622972-C-T

Variant names:

• chr16-23622972-C-T
• rs45551636
• NM_024675.4:c.2993G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024675.4(PALB2):​c.2993G>A​(p.Gly998Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 1,614,050 control chromosomes in the GnomAD database, including 389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G998V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (41 hom., cov: 32)
  • Exomes 𝑓: 0.020 (348 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:27 O:1
• Conservation: PhyloP100: 3.23
• Publications: 72 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

PALB2-AS1 (HGNC:58305):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 39 uncertain in NM_024675.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0049796402).
• BP6: Variant 16-23622972-C-T is Benign according to our data. Variant chr16-23622972-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 126699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0171 (2602/152274) while in subpopulation NFE AF = 0.0227 (1547/68026). AF 95% confidence interval is 0.0218. There are 41 homozygotes in GnomAd4. There are 1272 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 AR,AD gene

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.2993G>A	p.Gly998Glu	missense	Exon 9 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.2933G>A	p.Gly978Glu	missense	Exon 8 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.2921G>A	p.Gly974Glu	missense	Exon 8 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.2993G>A	p.Gly998Glu	missense	Exon 9 of 13	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.2108G>A	p.Gly703Glu	missense	Exon 9 of 13	ENSP00000454703.2	H3BN63
	PALB2	ENST00000561514.3	TSL:5	c.2999G>A	p.Gly1000Glu	missense	Exon 9 of 13	ENSP00000460666.3	A0AA52I2C1

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2605 AN: 152156 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.00459

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.0220

Gnomad ASJ AF: 0.0302

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00744

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0227

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0164 AC: 4123 AN: 251452 AF XY: 0.0168

Gnomad AFR exome AF: 0.00437

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.0232

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0188

Gnomad NFE exome AF: 0.0222

Gnomad OTH exome AF: 0.0212

GnomAD4 exome AF: 0.0199 AC: 29158 AN: 1461776 Hom.: 348 Cov.: 32 AF XY: 0.0198 AC XY: 14384 AN XY: 727196

African (AFR) AF: 0.00358 AC: 120 AN: 33478

American (AMR) AF: 0.0145 AC: 648 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0240 AC: 626 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.0101 AC: 872 AN: 86254

European-Finnish (FIN) AF: 0.0182 AC: 974 AN: 53410

Middle Eastern (MID) AF: 0.0366 AC: 211 AN: 5768

European-Non Finnish (NFE) AF: 0.0221 AC: 24539 AN: 1111924

Other (OTH) AF: 0.0193 AC: 1166 AN: 60394

GnomAD4 genome AF: 0.0171 AC: 2602 AN: 152274 Hom.: 41 Cov.: 32 AF XY: 0.0171 AC XY: 1272 AN XY: 74448

African (AFR) AF: 0.00457 AC: 190 AN: 41558

American (AMR) AF: 0.0219 AC: 335 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0302 AC: 105 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00745 AC: 36 AN: 4832

European-Finnish (FIN) AF: 0.0168 AC: 178 AN: 10602

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0227 AC: 1547 AN: 68026

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

Alfa AF: 0.0208 Hom.: 147

Bravo AF: 0.0177

TwinsUK AF: 0.0235 AC: 87

ALSPAC AF: 0.0205 AC: 79

ESP6500AA AF: 0.00592 AC: 26

ESP6500EA AF: 0.0240 AC: 206

ExAC AF: 0.0158 AC: 1917

Asia WGS AF: 0.00404 AC: 15 AN: 3478

EpiCase AF: 0.0306

EpiControl AF: 0.0278

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Familial cancer of breast (6)
-	-	6	not specified (7)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	5	not provided (5)
-	-	1	Breast-ovarian cancer, familial, susceptibility to, 5 (1)
-	-	1	Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 (1)
-	-	1	Fanconi anemia complementation group N (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)
1	-	-	Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.2
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Benign	0.29
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.28
MPC		0.38
ClinPred		0.012	T
GERP RS		5.8
Varity_R		0.80
gMVP		0.63
Mutation Taster		=77/23	polymorphism (auto)

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: rs45551636; hg19: chr16-23634293; COSMIC: COSV55161905; COSMIC: COSV55161905;