chr16-23634870-T-C

Variant names:

• chr16-23634870-T-C
• rs152451
• NM_024675.4:c.1676A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_024675.4(PALB2):​c.1676A>G​(p.Gln559Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0982 in 1,613,096 control chromosomes in the GnomAD database, including 8,861 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q559E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.13 (1527 hom., cov: 32)
  • Exomes 𝑓: 0.095 (7334 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23 O:1
• Conservation: PhyloP100: 0.387
• Publications: 81 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: ClinGen, Ambry Genetics
• Fanconi anemia complementation group N

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

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• familial ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

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 6 benign, 36 uncertain in NM_024675.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.005137205).
• BP6: Variant 16-23634870-T-C is Benign according to our data. Variant chr16-23634870-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 126613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

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.1676A>G	p.Gln559Arg	missense	Exon 4 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.1616A>G	p.Gln539Arg	missense	Exon 3 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.1676A>G	p.Gln559Arg	missense	Exon 4 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.1676A>G	p.Gln559Arg	missense	Exon 4 of 13	ENSP00000261584.4
	PALB2	ENST00000568219.5	TSL:1	c.791A>G	p.Gln264Arg	missense	Exon 4 of 13	ENSP00000454703.2
	PALB2	ENST00000561514.3	TSL:5	c.1682A>G	p.Gln561Arg	missense	Exon 4 of 13	ENSP00000460666.3

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19497 AN: 151978 Hom.: 1516 Cov.: 32

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.0979

Gnomad ASJ AF: 0.0907

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0928

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0884

Gnomad OTH AF: 0.127

GnomAD2 exomes AF: 0.104 AC: 26075 AN: 249632 AF XY: 0.103

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.0773

Gnomad ASJ exome AF: 0.0763

Gnomad EAS exome AF: 0.174

Gnomad FIN exome AF: 0.0960

Gnomad NFE exome AF: 0.0883

Gnomad OTH exome AF: 0.100

GnomAD4 exome AF: 0.0950 AC: 138857 AN: 1461000 Hom.: 7334 Cov.: 33 AF XY: 0.0953 AC XY: 69269 AN XY: 726738

African (AFR) AF: 0.218 AC: 7292 AN: 33452

American (AMR) AF: 0.0822 AC: 3668 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.0769 AC: 2009 AN: 26124

East Asian (EAS) AF: 0.192 AC: 7637 AN: 39690

South Asian (SAS) AF: 0.104 AC: 8973 AN: 86200

European-Finnish (FIN) AF: 0.0931 AC: 4967 AN: 53372

Middle Eastern (MID) AF: 0.127 AC: 733 AN: 5766

European-Non Finnish (NFE) AF: 0.0873 AC: 97026 AN: 1111420

Other (OTH) AF: 0.109 AC: 6552 AN: 60356

GnomAD4 genome AF: 0.129 AC: 19545 AN: 152096 Hom.: 1527 Cov.: 32 AF XY: 0.128 AC XY: 9543 AN XY: 74382

African (AFR) AF: 0.214 AC: 8874 AN: 41442

American (AMR) AF: 0.0977 AC: 1492 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0907 AC: 315 AN: 3472

East Asian (EAS) AF: 0.173 AC: 895 AN: 5178

South Asian (SAS) AF: 0.103 AC: 496 AN: 4824

European-Finnish (FIN) AF: 0.0928 AC: 983 AN: 10590

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.0884 AC: 6013 AN: 68004

Other (OTH) AF: 0.128 AC: 271 AN: 2110

Alfa AF: 0.105 Hom.: 2248

Bravo AF: 0.134

TwinsUK AF: 0.0879 AC: 326

ALSPAC AF: 0.0830 AC: 320

ESP6500AA AF: 0.221 AC: 970

ESP6500EA AF: 0.0909 AC: 782

ExAC AF: 0.106 AC: 12905

Asia WGS AF: 0.149 AC: 516 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (7)
-	-	4	Familial cancer of breast (4)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	4	not provided (4)
-	-	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	Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3;C5830615:Breast-ovarian cancer, familial, susceptibility to, 5 (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.40
DANN	Benign	0.094
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.41	N
PhyloP100		0.39
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.63	N
REVEL	Benign	0.023
Sift	Benign	1.0	T
Sift4G	Benign	0.87	T
Polyphen		0.0	B
Vest4		0.037
MPC		0.055
ClinPred		0.00026	T
GERP RS		-2.7
Varity_R		0.022
gMVP		0.11
Mutation Taster		=97/3	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: rs152451; hg19: chr16-23646191; COSMIC: COSV55161931; COSMIC: COSV55161931;